Use Pattern of Ophthalmic Antiglaucoma Agents with and without Preservatives: A Cross-Sectional Study

Background: Different drugs have been approved to reduce the intraocular pressure. However, most of them contain preservatives to maintain sterility and these can be toxic to the ocular surface. The aim was to determine the patterns of use of antiglaucoma agents and ophthalmic preservatives in a group of patients from Colombia. Methods: A cross-sectional study that identified ophthalmic antiglaucoma agents from a population database of 9.2 million. Sociodemographic and pharmacological variables were considered. Descriptive and bivariate analyses were performed. Results: A total of 38,262 patients were identified, with a mean age of 69.2 ± 13.3 years, and 58.6% were women. A total of 98.8% were prescribed antiglaucoma drugs in multidose containers. The most widely used were prostaglandin analogs (59.9%), especially latanoprost (51.6%) and β-blockers (59.2%). A total of 54.7% of patients received combined management, especially with fixed-dose combination (FDC) drugs (41.3%). A total of 94.1% used antiglaucoma drugs with preservatives (benzalkonium chloride, 68.4%). Conclusions: The pharmacological treatment of glaucoma was very heterogeneous, but the most commonly used therapeutic groups were in accordance with the recommendations of clinical practice guidelines but with differences by sex and age. Most of the patients were exposed to preservatives, especially benzalkonium chloride, but the wide use of FDC drugs can minimize toxicity on the ocular surface.


Introduction
Glaucoma is a chronic progressive optic neuropathy characterized by damage to the optic nerve and the nerve fibers of the retina leading to loss of peripheral vision and occasionally of central vision [1][2][3]. It is classified according to the anatomy of the anterior chamber angle (open: normal iridocorneal angle without iris occlusion; and closed: narrow iridocorneal angle with iris occlusion) or according to the rapidity of appearance (acute or chronic) and the etiology (primary/idiopathic or secondary) [2,4]. The global prevalence of glaucoma is 3.5% in people between 40 and 80 years of age, with open-angle glaucoma being the most common condition (3.1%), while closed-angle glaucoma is less frequent (0.5%) [5].
Glaucoma is one of the leading causes of blindness in the world [1,2,4]. The progression of this pathology is attenuated by decreasing intraocular pressure, which is achieved with topical medications and procedures such as laser trabeculoplasty and incisional surgery [1,4,[6][7][8]. First-line therapy is usually pharmacological, while the most invasive procedures are used in patients with an inadequate response to medications [4]. Some medications increase the output of aqueous humor from the eye (prostaglandin analogs -PGA-, α2-adrenergic agonists -AA-, and muscarinic agonists -MA-), and others decrease its production (AA, β-blockers -BB-and carbonic anhydrase inhibitors -CAI-), leading to a reduction in intraocular pressure [1,3,4,[6][7][8]. According to clinical practice guidelines, the initial pharmacological management should include PGAs and, as an alternative, BB. If these options are not tolerated or the objective of reducing intraocular pressure is not achieved, other therapeutic groups should be used, such as CAI, AA, or MA, or a combination of medications [6][7][8].
Preservatives are a requirement of eye drops in multidose containers to maintain sterility and avoid bacterial contamination [9,10]. Most preservatives act relatively nonspecifically as detergents or by oxidative mechanisms and therefore cause secondary effects on the ocular surface and periorbital structures [9,11,12]. Benzalkonium chloride (BAK) is the most widely used preservative in ophthalmology and is more toxic than other newer preservatives, such as Polyquad, Purite, and SofZia [9,11,12]. Ophthalmic preservatives, especially BAK, have been identified as implicated in the development of ocular surface disease [12,13]; its prevalence is between 49-59% [12], and this condition negatively impacts adherence to the antiglaucoma treatment regimen and the patient's quality of life [12,13]. Topical medication without preservatives could be recommended mainly for patients with ocular surface disease, severe or refractory glaucoma, a proven allergy to preservatives, and contact lenses, among others [10,12].
Knowledge of prescription patterns as evidence from the real world helps to assess the appropriate use of medications and the degree of adherence to the recommendations of clinical practice guidelines [14]. Its inappropriate use can lead to less effectiveness, greater adverse reactions, and increased costs [14]. Similarly, knowing the type of ophthalmic preservatives would provide information on the potential safety risk to which patients are exposed [12,13]. However, the information on the patterns of use of antiglaucoma drugs in the country is limited (BB and PGA predominate) [15], and the data available on the preservatives present in them are unknown. Internationally, there are few studies that address this topic, but it has been shown that most patients use antiglaucoma drugs with preservatives (84.0-96.0%); however, these reports do not characterize the type of preservative [16][17][18][19]. Another limitation of these studies is the low number of patients included [16][17][18][19]. The Colombian health system offers universal coverage to the entire population through two affiliation regimes: the contributory regime that is paid by workers and employers; and the subsidized regime that is responsible for the insurance of all people without the ability to pay, which has a benefit plan that includes a heterogeneous group of medications for the treatment of glaucoma. The objective of the study was to determine the patterns of use of antiglaucoma agents and ophthalmic preservatives present in these drugs in a group of patients affiliated with the Colombian Health System in 2022.

Ophthalmic Preservatives
Forty-nine different trade names for antiglaucoma medications were found, and the type of preservative could be determined in 85.7% of them. In seven products, the information on the type of preservative was not recorded on the label or in the technical data sheet of the drug. Thus, the majority of patients, 94.1% (n = 36,001), received antiglaucoma agents with preservatives. BAK predominated (n = 26,161; 68.4%), followed by sodium perborate (n = 492; 1.3%) and Polyquad (n = 135; 0.4%) (Tables 1-3). In 37.8% (n = 14,466), the type of preservative was unknown. A total of 88.7% (n = 33,934) of the patients received only antiglaucoma agents with preservatives, 5.9% (n = 2261) received only antiglaucoma agents free of preservatives, and 5.4% (n = 2067) received both antiglaucoma agents with preservatives and preservative-free.

Discussion
This study made it possible to characterize the prescription pattern of ophthalmic antiglaucoma drugs and the preservatives present in them as evidence of drug use in the real world in a group of patients affiliated with the Colombian Health System. These findings can be useful for health care, academic, and scientific personnel in making decisions regarding the risks faced by their patients. Further, these findings can contribute to strengthening the practices of the appropriate use of medications among physicians as a way to reduce problems related to their use in the country.
The average age of the patients in this study was similar to that found in other publications (67.1-72.0 years) [15][16][17]20,21]. However, it contrasts with some reports from Asian countries where the age was lower (55.0-61.3 years) [22,23]. Most of the patients were women, which is consistent with what is reported in the literature (54.2-72.9%) [15,17,20,21,24,25]. In this study, it was found that arterial hypertension and diabetes mellitus were the most common pathologies, which is consistent with other investigations [26][27][28]. High blood pressure and diabetes mellitus can contribute to the progression of glaucoma [29,30]. Cataracts were the most common ophthalmic comorbidity, as identified by Hwang et al., in Korea [26]. This pathology can induce pupillary blockage and occlusion of the iridocorneal angle, giving rise to closed-angle glaucoma, so its management is crucial in these patients [31].
PGAs were the most prescribed therapeutic group, especially in elderly individuals, which is consistent with other studies (48.0-58.8%) [16,20,25,32,33], but higher than that found in Taiwan and China (22.8% and 30.2%, respectively) [22,24]. Similarly, the most prescribed drug was latanoprost, as evidenced in other studies (28.0-50.0%) [20,24,34]. BB were also used with high frequency in this study, which was higher than that reported in the literature (9.4-44.1%) [16,22,32,33]. However, in general, the pattern of use of antiglaucoma agents is in line with the recommendations of the clinical practice guidelines, which suggest PGA as the first line of treatment or, failing that, BB [6][7][8].
Combination therapy with antiglaucoma agents predominated in this report, contrasting with other pharmacoepidemiological investigations where monotherapy prevailed (54.0-78.4%) [20,22,32,33]. This is probably due to the methodological differences used in the studies (e.g., type of study, way of identifying the cases, characteristics of the patients) [20,22,32,33], as our group of patients may have had a greater severity of the pathology. In this sense, men and increasing age have been associated with a greater risk of blindness and vision loss [31]. In this group of patients, therapy with various antiglaucoma agents predominated. Management with several medications requires that patients have multiple applications per day and poses difficulties in adherence and efficacy, as well as in safety due to greater exposure to preservatives [3,12]. However, in this report, the majority used FDC drugs, similar to findings described by Yan et al., in China (36.6%) [23] and very different from what was found in other studies (3.7-21.3%) [22,33]. The use of these drugs reduces the total amount of drops and preservatives applied per day, saves costs, improves tolerability and compliance, and prevents the washing effect that results from the sequential application of multiple drops [3,35].
The use of antiglaucoma agents with preservatives predominated widely in this report. The information available from studies with real-world evidence addressing this topic is limited [16][17][18][19]. However, in Germany, Wolfram et al., identified that 96.0% of patients with glaucoma used antiglaucoma agents with preservatives [18]. In France, Chamard et al., documented that 84.6% of patients with glaucoma were exposed to some preservative [16]. In Spain, Pérez-Bartolomé et al., described that 84.4% of glaucoma patients were exposed to preservatives [19]. Similarly, in Belgium, France, Italy, and Portugal, Jaenen et al., described that 84.0% of patients received antiglaucoma agents with preservatives [17]. In neither of the four investigations was the type of preservative characterized [16][17][18][19]. In a study carried out in Tunisia, 80.0% of the patients received antiglaucoma drugs with BAK [36]. In this report, a wide use of BAK was found, which is the most commonly used preservative in ophthalmology [9,11,21] and is linked to cytotoxic damage to the epithelial cells of the conjunctiva and cornea, which can lead to signs and symptoms of ocular surface disease [9,11] and contributes to the adherence and persistence of the use of antiglaucoma agents [10]. There are some strategies available to minimize exposure to BAK, such as (1) using alternative preservatives such as Polyquad, Purite, or SofZia (used in less than 2% of medications in this report), (2) using antiglaucoma agents without preservatives (used in little more than one-tenth of medications), (3) using FDC drugs in those who need to be managed with multiple drugs (used in three-quarters of medications in combination treatment), and (4) using drugs with the greatest efficacy (PGAs were used in more than half of the medications) [9,12].
It is striking that in some antiglaucoma patients, the type of preservative used was unknown. The regulations of the Food and Drug Administration (FDA) establish several elements that must be present in the information about medicines, such as active and inactive ingredients [37]. However, the local regulations in charge of the National Institute for Food and Drug Surveillance (INVIMA) are not very specific in this specific aspect [38]. This could explain the lack of data for some brands of antiglaucoma medications. Drug labeling is the primary tool for communicating essential information about the safe and effective use of a pharmaceutical product [39]. It is important that information on ophthalmic preservatives is available to medical personnel and the general population, so potential adverse reactions are known and can be prevented in patients with a history of hypersensitivity to the preservative and those who wear contact lenses [9,11,21].
Some limitations are recognized in the interpretation of the results, since access to medical records was not obtained to verify the clinical characteristics of the patients, such as the etiology of glaucoma, chronicity, severity, and complications, as well as the efficacy of the treatment and possible adverse drug reactions. Information from complementary studies such as tonometry, pachymetry, perimetry, gonioscopy, and ophthalmoscopy was not available. Similarly, the drugs prescribed outside the health system or not delivered by the dispensing company that the patients may have received are unknown. However, this study has a very important number of cases, distributed in most of the national territory, involving both the contributory and subsidized regimes of the country's health system.

Study Design and Patients
An observational cross-sectional study was carried out on the prescription patterns of antiglaucoma agents as well as the identification of their preservatives based on a database of approximately 9.2 million people affiliated with the Colombian Health System. The individuals were served by four health insurance companies, corresponding to approximately 25.3% of the active affiliated population of the contributory or payment scheme and 13.1% of the state-subsidized scheme, which comprise 18.8% of the Colombian population. The medication dispensing database contains sociodemographic variables (age, sex, dispensing city, and affiliation regime), pharmacological (medication, pharmaceutical shape, dose, and prescriber doctor), and main and secondary diagnoses [40,41]. This database is the most widely used source of secondary information for studies with evidence in the real world in Colombia, which allows for research on the use and safety of medications [41]. To date, more than 200 investigations have been carried out and published [40].
The identification of the patients was made from the dispensing of ophthalmic antiglaucoma drugs (BB, PGA, AA, CAI, and MA) from 1-31 October 2022. The drugs included were all those that were approved and that are marketed in the country. The first date of dispensing of the antiglaucoma was considered the patient's index date. Inclusion criteria: patients of any age, sex and origin were selected and received medical consultations as outpatients. Exclusion criteria: None.

Variables
Based on the information about the drug consumption of the affiliated population, which was systematically obtained from the dispensing company (Audifarma S.A., Colombia), a database was designed that allowed the following groups of patient variables to be collected:

1.
Sociodemographic: sex, age (<65 years and ≥65 years), health system affiliation regime (contributory or subsidized), and place of origin. The place of origin was categorized by departments according to the regions of Colombia, taking into account the classification of the National Administrative Department of Statistics (DANE), as follows: Bogotá-Cundinamarca region, Caribbean region, Central region, Eastern region, Pacific region, and Amazon-Orinoquía region; 2.
Clinical: The clinics identified the type of glaucoma and comorbidities in patients selected no more than 90 days from their index dates, using the codes of the International Classification of Diseases, version 10 (ICD-10). The type of glaucoma was categorized into closed-angle glaucoma (H402), open-angle glaucoma (H401), and unspecified glaucoma (H403-H406, H408, H409, H420, and H428); 3. Pharmacological: • Comedications: drugs prescribed in the 30 days following the index date were identified and grouped into the following categories: systemic comedications (antidiabetic, antihypertensive and diuretic, thyroid hormone, antiulcer, antidepressant and anxiolytic, analgesic and anti-inflammatory, antiepileptic, lipidlowering, among others) and ophthalmic comedications (ocular lubricants, antibiotics, corticosteroids, antihistamines, nonsteroidal anti-inflammatory drugs, and sympathomimetics, among others).

Ethical Statement
The protocol was approved by the Bioethics Committee of the Technological University of Pereira in the category of research without risk (Endorsement code: 03-091120). The ethical principles established by the Declaration of Helsinki were respected.

Data Analysis
The data were analyzed with the statistical package SPSS Statistics, version 26.0, for Windows (IBM, USA). Descriptive analysis was performed with frequencies and proportions for the qualitative variables and measures of central tendency and dispersion for the quantitative variables by means and standard deviation. The comparison of quantitative variables was performed using the Mann-Whitney U test and X 2 or Fisher's exact test for categorical variables. A level of statistical significance was established at p < 0.05.

Conclusions
With these findings, we can conclude that the pharmacological treatment was very heterogeneous, but the most commonly used therapeutic groups are in accordance with the recommendations of the clinical practice guidelines, albeit with differences by sex and age. Most of the patients were prescribed antiglaucoma drugs in multidose and were exposed to preservatives, especially benzalkonium chloride, that could contribute to the development of ocular surface disease, but the wide use of FDC drugs can minimize toxicity on the ocular surface. Funding: The present study did not receive funding.
Institutional Review Board Statement: The protocol was approved by the Bioethics Committee of the Universidad Tecnológica de Pereira (Technological University of Pereira) in the category of riskfree research (Endorsement code: 03-091120). The ethical principles established by the Declaration of Helsinki were respected.
Informed Consent Statement: Patient consent was waived due to the fact that the regulations in the country do not require it for risk-free investigations based on previously structured information.
Data Availability Statement: protocols.io.