Active surveillance of sodium hyaluronate 0.4% eyedrop: patient knowledge, adherence, and safety findings in real-world use

Active surveillance of sodium hyaluronate 0.4% eyedrop: patient knowledge, adherence, and safety findings in real-world use | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Active surveillance of sodium hyaluronate 0.4% eyedrop: patient knowledge, adherence, and safety findings in real-world use Miriam Guadalupe Becerra-Cota, Carlos Avalos-González, Liliana Gómez-Sánchez, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7704248/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Objective : This study aimed to evaluate the relationship between patient knowledge, educational level, and treatment adherence to sodium hyaluronate 0.4% eyedrops, while also identifying reported adverse events (AEs) in a real-world, post-authorization setting. Methods : A prospective, single-center, observational study was conducted with patients receiving sodium hyaluronate 0.4%. An initial in-person visit was followed by three follow-up phone calls (days 5, 15, and 30) to identify AEs and complete two questionnaires: the 8-item Morisky Green Medication Adherence Scale (MMAS-8) and the patient's knowledge of the study product. Results : Among 261 enrolled participants, 235 completed follow-ups. A clear association was found between product knowledge, educational level, and treatment adherence. Participants with higher education scored better on the knowledge survey and showed greater adherence. Less than 3% of the participants experienced AEs. The most frequently preferred term (PT) was eye irritation, with most AEs classified as mild and non-serious (88%). Conclusions : Health literacy emerged as a key determinant of adherence to 0.4% sodium hyaluronate eye drops, strongly linked to education and product knowledge. The study emphasizes the importance of patient education and active surveillance in optimizing adherence and ensuring the safe use of self-administered ophthalmic therapies. Adverse Event Artificial Tear Sodium Hyaluronate Patient's Knowledge Morisky Green Figures Figure 1 Figure 2 Figure 3 1. Introduction Artificial tears, commonly available as over-the-counter products, are the preferred treatment for dry eye disease. The solutions are typically hypo or isotonic and contain a combination of viscous agents, surfactants, and electrolytes, with or without preservatives. 1 The composition of artificial tears is compatible with maintaining normal ocular surface epithelium, thus improving the symptoms associated with tear instability. 2 – 4 Sodium hyaluronate, a glycosaminoglycan abundant in synovial fluid and vitreous humor, is one of the most commonly used viscous agents in artificial tears. Due to its chemical properties, sodium hyaluronate can effectively retain water, thereby providing lubrication to the ocular surface. 5 Its low toxicity, non-immunogenicity, and lack of genotoxicity contribute to its safety in various ophthalmic formulations. 6 Furthermore, experimental studies have demonstrated that sodium hyaluronate does not alter the normal conjunctival epithelium, interfere with the secretion processes of goblet cells, or damage the intercellular junctions, in contrast to other artificial tears solutions. 7 Although sodium hyaluronate is considered secure, it is essential to gather longitudinal data to corroborate its long-term safety further. 8 Ongoing safety evaluation, conducted through pharmacovigilance, relies on both active and passive surveillance methods. Passive surveillance serves as the foundation of pharmacovigilance, but it is mainly dependent on the voluntary reporting of adverse events (AEs), which is often less prevalent in ophthalmology compared to other medical specialties. 9,10 11 Therefore, active surveillance methods, such as post-authorization safety studies, 8 are frequently employed. PASS includes both clinical trials and observational studies. Observational studies are particularly valuable in identifying, quantifying, and characterizing safety risks (such as AEs, product misuse due to insufficient knowledge, and issues related to treatment adherence), thereby complementing the safety profile and assessing the effectiveness of risk minimization measures. 12 To date, there is limited information regarding the use of 0.4% sodium hyaluronate in an uncontrolled population. Therefore, our study presents the findings of an uncontrolled post-authorization safety study of 0.4% sodium hyaluronate, focusing on treatment adherence, user knowledge of the product, and AEs. 2. Methods 2.1. Study design. We conducted a prospective, single-center, uncontrolled observational post-authorization study that involved an initial in-person visit (day 0) and three follow-up phone calls (days 5, 15, and 30). 2.2. Study population This study included patients over 18 years or older who were prescribed sodium hyaluronate 0.4% for the first time as a new indication and attended the ophthalmology service at the "Hospital Civil de Guadalajara, Fray Antonio Alcalde,” in Guadalajara, México." 2.3. Data collection Patients were invited to participate in the study after an ophthalmologist diagnosed them with dry eye and deemed treatment necessary. They were prescribed 0.4% sodium hyaluronate eye drops in a dosage tailored to each patient's specific needs. After obtaining informed consent, the patient's telephone number and medical history were recorded during the initial visit. Subsequently, 5 ± 2 days after the initial visit, sociodemographic and AEs were inquired (first call). At 15 ± 2 days, only the verification of AE was conducted (second call). Finally, 30 ± 2 days later, in addition to verifying AEs, the Morisky Green 8-item survey and the patient's knowledge of the study product were applied (third call). The data were collected between November 2023 to September 2024. 2.4. Outcome Variables The primary outcomes of this study included both surveys: patients' knowledge of the study product and treatment adherence, using the 8-item Morisky Medication Adherence Scale (MMAS-8). These outcomes were selected to explore cognitive and behavioral factors that may influence treatment use in clinical practice and patient participation. Secondary outcomes included the incidence, severity, seriousness and causality of AEs reported during follow-up. 2.5. Categorization The patient population was classified into two age groups: adults (18–64 years) and elderly (65 years and older). The level of education was categorized as follows: unfinished elementary school, elementary (grades 1 to 6), middle school (grades 7 to 10), high school (grades 10 to 12), and higher education (bachelor´s degree, master´s degree, or PhD). In turn, the severity of the ADRs was assessed using the ADR Severity Assessment Scale (Modified Hartwig and Siegel). 13 , 14 Subsequently, the ADRs' causal relationships were evaluated per the Naranjo algorithm (Definite, Probable, Possible, Doubtful, and Not Assessable). 15 All ADRs were listed according to MedDRA v27.1 (Medical Dictionary for Regulatory Activities). Finally, seriousness (serious / non-serious) was evaluated by its likeliness to cause permanent damage, life-threatening, or death, according to the International Conference on Harmonisation (ICH). 16 2.6. Patient knowledge of the treatment Patient knowledge about the product will be assessed using the questionnaire by García-Delgado et al ., which consists of 11 questions, each of which evaluates an essential aspect of the points mentioned below: indication, dose, posology, treatment duration, administration, precaution, AEs, contraindications, effectiveness, interactions and conservation. 17 Once the survey data is obtained, the interviewer categorizes the responses regarding the Summary of Product Characteristics (SmPC) into three categories: correct, incorrect, and don’t know. 2.7. Morisky Green (MMAS) test An adapted version of the Morisky Medication Adherence Scale for use in the Spanish population will be utilized to evaluate medication adherence. This assessment consists of eight items that require a dichotomous yes/no response, reflecting the patient's behavior regarding compliance. This test aims to determine whether the patient demonstrates appropriate attitudes toward their treatment. It is assumed that patients with incorrect attitudes may be non-compliant with their prescribed treatment (≤ 5 low adherence, 6 to 7 moderate adherence and > 8 high adherence). 18 – 20 2.8. Statistical analyses All data were evaluated using exploratory data analysis, which encompassed descriptive statistics. This included frequency distributions presented in tables, diagrams, and histograms. The results were displayed through both qualitative and quantitative descriptions, utilizing measures such as the mean (± SD) for numerical data and frequencies with percentages for categorical data. For the comparison among schooling, patient knowledge, and adherence, statistical methods were selected based on the distribution and scale of the variables as follows: Since normality was not achieved according to the Shapiro-Wilk test (p > 0.05), non-parametric methods were employed. When categorical variables were compared with ordinal or discrete variables, the Kruskal-Wallis test was used. If significant differences were identified, post hoc analyses were conducted using Dunn’s test with Bonferroni correction to control for Type I error in multiple comparisons. When both variables were categorical, associations were assessed using the chi-square test of independence. For significant chi-square results, post hoc examinations of standardized adjusted residuals were conducted to identify specific contributions, using Bonferroni-adjusted p-values to account for multiple testing. All analyses were performed using RStudio (version 2024.12.0), with significance set at p < 0.05. 3. Results 3.1. Baseline and demographic characteristics. Two hundred sixty-one subjects were recruited, with 10% of losses (3 screening failures and 23 losses to follow-up), a total of 235 subjects were completed (154 females and 81 males). The average age of the finished subjects was 53.99 ± 18.78 (adult n = 151, 64% and elderly n = 84, 46%). An 18-week pregnant woman was included in the study. No breastfeeding subjects were enrolled. The educational levels of the study subjects were as follows: unfinished elementary (n = 36; 15%), elementary (n = 57; 24%), middle school (n = 37; 16%), high school (n = 57; 24%), and superior grades (n = 48; 21%). The highest incidence of comorbidities in the study were: hypertension (n = 55), diabetes (n = 46), cataracts (n = 11), hypothyroidism (n = 8) and rheumatoid arthritis (n = 7). Regarding concomitant medications, the most frequent were hypoglycemic agents, such as metformin (n = 40) and insulin (n = 31), followed by antihypertensives, including losartan (n = 26), telmisartan (n = 12), amlodipine (n = 6), and enalapril (n = 6); finally, the synthetic hormone levothyroxine (n = 11). 3.2. Morisky Green (MMAS) test In the Morisky Green test, it was observed that most of the study subjects obtained a score of moderate adherences (44%) followed by high (32%) and finally low (24%). A detailed analysis of the data showed that 49% of the patients forgot to use the product at some point during the treatment (MMAS1) and 32% of the subjects forgot to use the product at least once in the 2 weeks before the survey (MMAS2); on the contrary, only 1% of the respondents feel pressured to continue the treatment for their problem (MMAS7) or have reduced the dose or stopped using the product without telling their doctor because they felt worse when using the product (MMAS3) (Fig. 1 ). Furthermore, the data indicated a direct relationship between product education level and treatment adherence, as illustrated in Fig. 2 B. Participants who answered more questions correctly tended to have higher adherence rates, which was also correlated with an increased level of education among the subjects. A chi-square test was conducted to evaluate the association between educational level and treatment adherence. The results revealed a statistically significant association (χ²(df = 8) = 22.659, p = 0.00383). Post hoc analysis based on standardized adjusted residuals revealed a significant overrepresentation in the unfinished elementary school and low adherence group (p = 0.0056) and a trend toward higher education and high adherence" combination (p = 0.0546) (Supplementary material 1). 3.3. Patient knowledge of the treatment. The participants achieved a median score of 7 out of 10 on the product knowledge questionnaire, with scores ranging between 5 and 10. Figure 3 illustrates the subjects' knowledge across the various sections outlined in the methodology. Notably, 100% of participants answered correctly regarding the product's "dose" and "posology." In contrast, knowledge related to "interactions" (0%), "AEs" (9%), and "contraindications” (10%) had the lowest response rate, indicating that these areas were the least understood by the subjects. Similar to the association between education level and treatment adherence, there is also a correlation between product knowledge, education level, and treatment adherence (Fig. 2 A). A Kruskal-Wallis test was performed to examine differences in product knowledge across educational levels. The test showed a highly significant effect (H(df = 4) = 24.038, p < 0.001). Post hoc comparisons revealed significant differences between "Higher education" and "Elementary" (p = 0.003) and between "Higher education" and "Middle school" (p = 0.0088). The comparison between "Higher education" and "Unfinished elementary school" showed a suggestive trend (p = 0.036) but was not statistically significant. This indicates that the higher the educational level, the greater the knowledge about the product. Besides, the Kruskal-Wallis test examining the relationship between product knowledge and adherence also showed statistically significant differences (H(df = 2) = 12.512, p = 0.002). Dunn's post hoc analysis revealed significant differences between the "High knowledge – Low adherence" group (p = 0.050) and the "High knowledge – Medium adherence" group (p = 0.008), indicating that increased product knowledge was associated with improved adherence (Supplementary material 1). 3.4. Adverse events Of the two hundred sixty-one patients, only 7 (8 EAs), representing less than 3% of the total participants. Table 1 outlines the characteristics of these subjects. The average age of the participants was 54.9 years ± 19.0, and the majority were female (63%). The most frequently reported system organ class (SOC) was ocular disorders, occurring in 63% of cases, with the preferred term (PT) of eye irritation affecting 25% of subjects. Most cases were classified as mild and not serious (88%), with only one considered serious. The causality was assessed as possible in 63% of the cases. Additionally, the PTs nasal congestion, eye pruritus, and dry eye were categorized as unexpected events. 4. Discussion In this study, a strong relationship was observed between patients’ product knowledge and their treatment adherence, as reflected in the adherence scores and educational background of the participants. Several studies support the notion that patient empowerment and awareness regarding their medication, as well as socioeconomic status, significantly influence the disease management of their condition. 21 – 23 Moreover, our results indicate that educational level plays a crucial role in adherence, a finding consistent with previous reports that have linked low educational attainment to poor treatment compliance. 24 – 27 Nonetheless, Okuno et al. and Yavuz et al., mention that additional factors influencing, including cognitive impairment, limited communication with healthcare professionals, low perception of treatment benefit, poor motivation, socioeconomic constraints, and lack of social or familial support. 25 , 27 As previously mentioned, our findings revealed an association between educational attainment and treatment adherence, with notably lower adherence among participants with unfinished elementary education (p = 0.0056). In comparison, higher education levels tended to correlate with better adherence. Furthermore, product knowledge was significantly higher among participants with higher education (p < 0.001), and this knowledge was positively associated with adherence (p = 0.002). These relationships are particularly relevant when interpreted in conjunction with the pharmacovigilance data. Despite specifically screening patients for AEs, the pharmacovigilance data revealed notably low rates (< 3%). This rate is considerably lower than that observed in other studies utilizing sodium hyaluronate formulations. 1,28 The low incidence of AEs may initially appear favorable, but it could reflect an underestimation influenced by participants' limited awareness of risks, this is consistent with our findings that indicated where only 9% of patients were aware of adverse drug reactions. The significantly lower adherence observed among individuals with unfinished elementary education likely reflects structural barriers such as low health literacy, limited access to information, and socioeconomic disadvantage, factors widely documented as contributors to poor adherence. 24 – 27 Besides, participants with higher education demonstrated greater knowledge about the product and a corresponding increase in adherence, supporting the well-established link between patient education and treatment engagement. The results suggest that poor adherence and underreporting may share a common origin. These insights underscore the clinical significance of implementing targeted educational strategies, particularly in vulnerable populations, not only to enhance adherence but also to improve the accuracy of safety data collection and promote patient empowerment in therapeutic decision-making. Regarding the reported AEs, ocular irritation was classified as infrequent according to the CIOMS classification, whereas the product monograph lists it as a frequent adverse reaction. 29 Furthermore, blurred vision, commonly reported with artificial tears, was not observed in any case. The disparity between expected and observed AEs suggests underreporting, which is likely due to patients' limited knowledge and recognition of potential adverse effects. This phenomenon is consistent with previous findings indicating that inadequate understanding contributes to the underreporting of AEs in pharmacovigilance. 11 , 30 , 31 In addition, three were classified as unexpected: nasal congestion, ocular itching, and dry eye; however, the causality was low (doubtful and possible). No references in the literature or the product’s Summary of Product Characteristics (SmPC) associate sodium hyaluronate or artificial tears with nasal congestion or eye pruritus, 32–37 which could indicate that there is no causal relationship between the event and the drug. However, these reports may also reflect limited patient awareness of expected adverse effects, potentially leading to misattribution or overreporting of unrelated symptoms. About dry eye, this condition indicates a lack of therapeutic effectiveness rather than a side effect of the treatment. The product, which is not approved for use in patients with severe dry eye, may not be sufficient to alleviate symptoms in specific individuals. Although various authors mention tachyphylaxis, such as therapeutic inefficacy or lack of efficacy, 38–40 most SmPCs do not list ineffectiveness as an adverse drug reaction. This is particularly true when pharmacological action is present but insufficient due to the progression or severity of the disease. For example, it would be inappropriate to label an NSAID as ineffective in patients requiring opioids for severe pain, or to classify a hypoglycemic agent as ineffective in cases where disease advancement necessitates insulin. Similarly, the absence of a clinical response to sodium hyaluronate in certain patients may reflect a limitation in therapeutic scope rather than an unexpected safety concern. 5. Limitations of the Study This study has some limitations. The use of structured surveys to assess knowledge and adherence may be subject to recall or response bias. Despite this, the findings highlight the importance of patient education in improving adherence and the quality of pharmacovigilance data. 6. Conclusion The present study provides valuable information on patient behavior and pharmacovigilance related to 0.4% sodium hyaluronate eye drops. A strong and consistent association was found between educational level, product knowledge, and treatment adherence, underscoring the vital role of health literacy in achieving optimal therapeutic outcomes. The findings emphasize the need to integrate patient education strategies to improve therapeutic adherence and ensure safe medication use, particularly for self-administered ophthalmic treatments. Although the reported incidence of AEs was lower than that indicated in the SmPC for similar products, this may reflect underreporting due to a lack of patient awareness rather than a genuinely lower incidence. Overall, this study emphasizes the importance of active surveillance methods that not only monitor AEs but also investigate patient-level factors affecting real-world medication use. Declarations Data Availability Statement The data is available upon request from the corresponding author. Ethics Approval Statement This study and the informed consent process were approved by the Investigation Committee (Approval number CI-1381/22) and the Research Ethics Committee (Approval number CEI-1378/22) of the Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde, located in Guadalajara, Mexico. All participants were given a comprehensive explanation of the study and provided written informed consent. The present study was conducted in accordance with the standards of the Declaration of Helsinki, the Nuremberg Code, the Belmont Report, and the International Ethical Guidelines for Epidemiological Studies of the Council for International Organizations of Medical Sciences (CIOMS). Consent for Publication Not Applicable Conflict of Interest Laboratorios Sophia, S.A. de C.V. provided salary support for authors H. C-S, J.C.V-B, and L.Y. R-H, but did not have any additional role in the data collection. Funding This study was sponsored by Laboratorios Sophia, S.A. de C.V. (Zapopan, Jalisco, México). Acknowledgment The authors thank Dr. Sarahi del Carmen Gomez Macias for her assistance writing the medical manuscript. Copyright US Copyright laws protect the use of the ©MMAS. The authors have obtained permission to use the 8-item Morisky Medication Adherence Scale (Supplementary material 2). References Contreras-Salinas H, Barajas-Hernández M, Baiza-Durán LM, Orozco-Ceja V, Rodríguez-Herrera LY. Ophthalmic solution safety profile: Active surveillance of a sodium hyaluronate/chondroitin sulfate combination in peruvian population. Drug Healthc Patient Saf. 2021;13:117–23. 10.2147/DHPS.S311817 . Phadatare SP, Momin M, Nighojkar P, Askarkar S, Singh KK. A Comprehensive Review on Dry Eye Disease: Diagnosis, Medical Management, Recent Developments, and Future Challenges. Adv Pharm. 2015;2015(1):704946. https://doi.org/10.1155/2015/704946 . Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II Report Executive Summary. Ocul Surf. 2017;15(4):802–12. 10.1016/j.jtos.2017.08.003 . Aragona P, Papa V, Micali A, Santocono M, Milazzo G. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol. 2002;86(2):181–4. 10.1136/bjo.86.2.181 . Shimmura S, Ono M, Shinozaki K, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol. 1995;79(11):1007–11. 10.1136/bjo.79.11.1007 . Becker LC, Bergfeld WF, Belsito DV, et al. Final Report of the Safety Assessment of Hyaluronic Acid, Potassium Hyaluronate, and Sodium Hyaluronate. Int J Toxicol. 2009;28(4suppl):5–67. 10.1177/1091581809337738 . Aragona P, Di Stefano G, Ferreri F, Spinella R, Stilo A. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren’s syndrome patients. Br J Ophthalmol. 2002;86(8):879–84. 10.1136/bjo.86.8.879 . Lucas S, Ailani J, Smith TR, Abdrabboh A, Xue F, Navetta MS. Pharmacovigilance: reporting requirements throughout a product’s lifecycle. Ther Adv drug Saf. 2022;13:20420986221125010. 10.1177/20420986221125006 . Mwakawanga DL, Kilonzi M, Philipo EG, et al. Pharmacovigilance and Adverse Drug Reactions Reporting: Healthcare Providers’ Experiences from Southern Highland Tanzania. Adv Pharmacol Pharm Sci. 2023;2023:5537592. 10.1155/2023/5537592 . Lomeli-Silva A, Contreras-Salinas H, Barajas-Virgen MY, Romero-Lopez MS, Rodríguez-Herrera LY. Harmonization of individual case safety reports transmission requirements among PAHO reference authorities: a review of their current regulation. Ther Adv Drug Saf. 2024;15:20420986241228120. 10.1177/20420986241228119 . Contreras-Salinas H, Baiza-Durán LM, Bautista-Castro MA, Alonso-Rodríguez DR, Rodríguez-Herrera LY. Underreporting and Triggering Factors for Reporting ADRs of Two Ophthalmic Drugs: A Comparison between Spontaneous Reports and Active Pharmacovigilance Databases. Healthc (Basel Switzerland). 2022;10(11). 10.3390/healthcare10112182 . European Medicines Agency (EMA). Post-authorisation safety studies (PASS). Accessed August 20. 2024. https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/post-authorisation-safety-studies-pass Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm. 1992;49(9):2229–32. Petrova G, Stoimenova A, Dimitrova M, Kamusheva M, Petrova D, Georgiev O. Assessment of the expectancy, seriousness and severity of adverse drug reactions reported for chronic obstructive pulmonary disease therapy. SAGE open Med. 2017;5:2050312117690404. 10.1177/2050312117690404 . Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45. 10.1038/clpt.1981.154 . International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH). Maintenance of the ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports E2B (R2). 2001. https://admin.ich.org/sites/default/files/inline-files/E2B_R2_Guideline.pdf García Delgado P, Gastelurrutia Garralda MA, Baena Parejo MI, Fisac Lozano F, Martínez Martínez F. [Validation of a questionnaire to assess patient knowledge of their medicines]. Aten primaria. 2009;41(12):661–8. 10.1016/j.aprim.2009.03.011 . Martinez-Perez P, Orozco-Beltrán D, Pomares-Gomez F, et al. Validation and psychometric properties of the 8-item Morisky Medication Adherence Scale (MMAS-8) in type 2 diabetes patients in Spain. Atención Primaria. 2021;53(2). 10.1016/j.aprim.2020.09.007 . Medina-Rodríguez JC, Lugo-Bautista KS, Consistency. Reliability, and Validation of the 8-Item Morisky Medication Adherence Scale in Mexican Patients with Depressive Disorders and Type 2 Diabetes Mellitus. Rev la Asoc Psiquiatr Mex. 2024;4(2):27–38. Krousel-Wood M, Islam T, Webber LS, Re RN, Morisky DE, Muntner P. New medication adherence scale versus pharmacy fill rates in seniors with hypertension. Am J Manag Care. 2009;15(1):59–66. Taibanguay N, Chaiamnuay S, Asavatanabodee P, Narongroeknawin P. Effect of patient education on medication adherence of patients with rheumatoid arthritis: a randomized controlled trial. Patient Prefer Adherence. 2019;13:119–29. 10.2147/PPA.S192008 . Jin J, Sklar GE, Min Sen Oh V, Chuen Li S. Factors affecting therapeutic compliance: A review from the patient’s perspective. Ther Clin Risk Manag. 2008;4(1):269–86. 10.2147/tcrm.s1458 . Thummak S, Uppor W, Wannarit LO. Patient compliance: A concept analysis. Belitung Nurs J. 2023;9(5):421–7. 10.33546/bnj.2807 . Apter AJ, Boston RC, George M, et al. Modifiable barriers to adherence to inhaled steroids among adults with asthma: it’s not just black and white. J Allergy Clin Immunol. 2003;111(6):1219–26. 10.1067/mai.2003.1479 . Okuno J, Yanagi H, Tomura S. Is cognitive impairment a risk factor for poor compliance among Japanese elderly in the community? Eur J Clin Pharmacol. 2001;57(8):589–94. 10.1007/s002280100347 . Ghods AJ, Nasrollahzadeh D. Noncompliance with immunnosuppressive medications after renal transplantation. Exp Clin Transpl Off J Middle East Soc Organ Transpl. 2003;1(1):39–47. Yavuz A, Tuncer M, Erdoğan O et al. Is there any effect of compliance on clinical parameters of renal transplant recipients? Transplant Proc . 2004;36(1):120–121. 10.1016/j.transproceed.2003.11.052 Belalcázar-Rey S, Sánchez Huerta V, Ochoa-Tabares JC, et al. Efficacy and Safety of Sodium Hyaluronate/chondroitin Sulfate Preservative-free Ophthalmic Solution in the Treatment of Dry Eye: A Clinical Trial. Curr Eye Res. 2021;46(7):919–29. 10.1080/02713683.2020.1849733 . de Laboratorios Sophia SA. C.V. Monografía Lagricel Ofteno . Costa C, Abeijon P, Rodrigues DA, Figueiras A, Herdeiro MT, Torre C. Factors associated with underreporting of adverse drug reactions by patients: a systematic review. Int J Clin Pharm. 2023;45(6):1349–58. 10.1007/s11096-023-01592-y . Matos C, van Hunsel F, Joaquim J. Are consumers ready to take part in the Pharmacovigilance System?--a Portuguese preliminary study concerning ADR reporting. Eur J Clin Pharmacol. 2015;71(7):883–90. 10.1007/s00228-015-1867-2 . Bausch. & Lomb. Minims Artificial Tears, Eye drops solution. 2018. Accessed January 28, 2025. https://www.medicines.org.uk/emc/product/3737/smpc/print AvKARE, ARTIFICIAL TEARS- artificial tears solution/ drops. 2024. Accessed January 28, 2025. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f18bebf2-1936-658f-e053-2a95a90a5012 Vizulize. VIZhyal 0.4% Product Information. 2019. https://www.vizulize.com/wp-content/uploads/2019/07/VIZhyal-0.4-product-information-1.pdf Pharma Stulln GmbH. Hylan 0,15/0,15 mg/ml. 2015. Accessed January 26, 2025. https://www.geneesmiddeleninformatiebank.nl/smpc/h115288_smpc.pdf URSAPHARM Arzneimittel GmbH, HYCOSAN® EXTRA., Accessed. January 25, 2025. https://dryeyes.help/wp-content/uploads/2021/01/Hycosan-Extra-Patient-Information-Leaflet.pdf TRB CHEMEDICA. Summary of product characteristics VISMED® MULTI. 2017. https://trbchemedica.co.uk/blogs/dry-eye-product-smpcs/vismed-multi-smpc Meyboom RH, Lindquist M, Flygare AK, Biriell C, Edwards IR. The value of reporting therapeutic ineffectiveness as an adverse drug reaction. Drug Saf. 2000;23(2):95–9. 10.2165/00002018-200023020-00001 . Figueras A, Pedrós C, Valsecia M, Laporte JR. Therapeutic Ineffectiveness. Drug Saf. 2002;25(7):485–7. 10.2165/00002018-200225070-00002 . Franceschi A, Tuccori M, Bocci G, et al. Drug therapeutic failures in emergency department patients. A university hospital experience. Pharmacol Res. 2004;49(1):85–91. 10.1016/j.phrs.2003.08.001 . Tables Table 1. Adverse events Age (Yeas) Sex Posology Comorbidities Concomitants Event PT SOC Causality Expectedness Severity Seriousness 62 F 1 drop each 4h Rheumatoid arthritis Vitamin D Nasal congestion Nasal congestion Respiratory, thoracic and mediastinal disorders Doubtful No Mild No Itchy ears Ear pruritus Ear and labyrinth disorders Possible No Mild No 74 M 1 drop each 4h Hypertension Amlodipine Ocular irritation Eye irritation Eye disorders Possible Yes Mild No Losartan Atorvastatin Dapagliflozin Metoprolol Propafenone Metformin 58 F 1 drop each 4h N/A N/A Ocular pruritus Eye pruritus Eye disorders Possible Yes Mild No 50 F 1 drop each 12h Chronic kidney disease Prednisone Ocular irritation Eye irritation Eye disorders Probable Yes Mild No Apixaban Tacrolimus Mycophenolic Acid Nitrofurantoin 45 F 1 drop each 4h Cataract surgery N/A Dry eye Dry eye Eye disorders Possible No Mild No 20 F 1 drop each 4h Dysautonomia N/A Allergic reaction Hypersensitivity Immune system disorders Possible Yes Severe Yes 75 M 2 drop each 4h Cataract Losartan Tearing Lacrimation increased Eye disorders Probable Yes Mild No Diabetes Mellitus II Metoprolol Atorvastatin Hypertension Metformin Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial1..docx Supplementarymaterial2.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 17 Dec, 2025 Reviewers agreed at journal 07 Dec, 2025 Reviewers invited by journal 02 Oct, 2025 Editor assigned by journal 02 Oct, 2025 Editor invited by journal 30 Sep, 2025 Submission checks completed at journal 29 Sep, 2025 First submitted to journal 29 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7704248","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":528333535,"identity":"21ec4425-12c0-4fe6-a2ba-b244fa93ef54","order_by":0,"name":"Miriam Guadalupe Becerra-Cota","email":"","orcid":"","institution":"Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde","correspondingAuthor":false,"prefix":"","firstName":"Miriam","middleName":"Guadalupe","lastName":"Becerra-Cota","suffix":""},{"id":528333536,"identity":"34d33edc-da05-4e14-881f-3832405fd5da","order_by":1,"name":"Carlos Avalos-González","email":"","orcid":"","institution":"Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"","lastName":"Avalos-González","suffix":""},{"id":528333537,"identity":"43d4d149-7c09-4fc5-9f85-6609263ffce4","order_by":2,"name":"Liliana Gómez-Sánchez","email":"","orcid":"","institution":"Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde","correspondingAuthor":false,"prefix":"","firstName":"Liliana","middleName":"","lastName":"Gómez-Sánchez","suffix":""},{"id":528333538,"identity":"fc280a40-1902-44a4-8551-405b2d2f9b15","order_by":3,"name":"Janet Cristina Vázquez-Beltrán","email":"","orcid":"","institution":"Laboratorios Sophia, S.A. de C.V. Zapopan","correspondingAuthor":false,"prefix":"","firstName":"Janet","middleName":"Cristina","lastName":"Vázquez-Beltrán","suffix":""},{"id":528333539,"identity":"c780bc37-d43c-42e5-a624-1285e954ea88","order_by":4,"name":"Lourdes Yolotzin Rodríguez-Herrera","email":"","orcid":"","institution":"Laboratorios Sophia, S.A. de C.V. Zapopan","correspondingAuthor":false,"prefix":"","firstName":"Lourdes","middleName":"Yolotzin","lastName":"Rodríguez-Herrera","suffix":""},{"id":528333540,"identity":"d8665e5a-bdb2-406c-8083-af199b2ce1f0","order_by":5,"name":"Homero Contreras-Salinas","email":"data:image/png;base64,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","orcid":"","institution":"Laboratorios Sophia, S.A. de C.V. Zapopan","correspondingAuthor":true,"prefix":"","firstName":"Homero","middleName":"","lastName":"Contreras-Salinas","suffix":""}],"badges":[],"createdAt":"2025-09-24 13:38:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7704248/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7704248/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93638586,"identity":"a43e01ca-6381-47a2-8400-9344d8279dc9","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":29429,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/aefb8634de290a64343f1ec6.docx"},{"id":93638591,"identity":"b253082e-5eda-40ab-baec-357add85ce40","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":83816,"visible":true,"origin":"","legend":"","description":"","filename":"LagricelmanusciptBMC.docx","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/ef0a970c110789e6d2b70a1d.docx"},{"id":93638597,"identity":"6137e59b-5512-40db-8b24-4dc11d896ec2","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":221363,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/09d4104327f883cfddc3459d.docx"},{"id":93639271,"identity":"67cb6339-eea1-43c1-88b4-3de5128af3b1","added_by":"auto","created_at":"2025-10-16 02:06:36","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":29019,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/3f7b9d0f80d1ed49ae7446dd.docx"},{"id":93639274,"identity":"65811f67-f199-43ce-9700-3c28a8f75731","added_by":"auto","created_at":"2025-10-16 02:06:36","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20640,"visible":true,"origin":"","legend":"","description":"","filename":"Table1..docx","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/8f8e8f8966e93a9a80c72d3e.docx"},{"id":93638599,"identity":"1c1bd30f-3d64-4e97-bc69-a5b5ec54f38c","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"json","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7450,"visible":true,"origin":"","legend":"","description":"","filename":"e235a8f905174e03af6f436dfffbf15f.json","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/457b749b9c3ccde3e40969a8.json"},{"id":93639772,"identity":"826045af-4667-43e2-bf03-6000afa286c3","added_by":"auto","created_at":"2025-10-16 02:14:36","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20544,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial1..docx","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/00094ada91555fb2c4578017.docx"},{"id":93639275,"identity":"94e3be09-561a-4535-8e4e-4e3a9efc0f2e","added_by":"auto","created_at":"2025-10-16 02:06:36","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":285511,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/745efcdd2cff1d7cf601dccf.pdf"},{"id":93639278,"identity":"2fea107f-0f53-4e08-8497-b00c9ceed4de","added_by":"auto","created_at":"2025-10-16 02:06:36","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":105924,"visible":true,"origin":"","legend":"","description":"","filename":"e235a8f905174e03af6f436dfffbf15f1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/3d34ea1d7aac682bf3451052.xml"},{"id":93639770,"identity":"567acd57-b50f-4250-8501-9f75b8fc3422","added_by":"auto","created_at":"2025-10-16 02:14:36","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12993,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/43facaa8ac3c1b8e23a18d3a.png"},{"id":93638605,"identity":"2219596b-dda5-456d-8efb-6de5c23dd583","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":205554,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/5a5e5dc687e7f34f7711f61d.png"},{"id":93638604,"identity":"1f03d7b5-f8c3-4621-86cc-257e10002fe5","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/85b030e477b8bc9bb416f91c.jpeg"},{"id":93638600,"identity":"df8f4705-47eb-4445-a736-f04655818ecc","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12468,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/1dd32ccb22eacf1a94bc5558.png"},{"id":93638603,"identity":"0585b4bc-ce4a-4a98-8a43-5ce8912345bf","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":13614,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/c634b1ab5e84d6a220784396.png"},{"id":93638598,"identity":"5e784860-9cf6-4e40-8a9e-e8825279d634","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37919,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/b7ec5df33d631c0141446773.png"},{"id":93638608,"identity":"a8cbbfc2-e051-4e25-b9f2-20d42fc9593c","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/7bcedd479a76f87436aa9cdf.png"},{"id":93638609,"identity":"4b40e82c-5677-4c29-9934-7a9a6fc3300f","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12822,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/57da9d9e88da46d7625129b7.png"},{"id":93638607,"identity":"f2cf9cd5-f825-40a0-84a0-bae208b735ae","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"xml","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":102042,"visible":true,"origin":"","legend":"","description":"","filename":"e235a8f905174e03af6f436dfffbf15f1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/2d77b1f657b8b7300c3e4bb9.xml"},{"id":93639277,"identity":"d3975525-d436-4984-a4d7-f08d0950e338","added_by":"auto","created_at":"2025-10-16 02:06:36","extension":"html","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":114524,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/11233098bce7e3b988d1c0e4.html"},{"id":93638590,"identity":"df42a33b-d50f-4487-b2d2-a8f20b857d2c","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":105461,"visible":true,"origin":"","legend":"\u003cp\u003eMorisky Green´s treatment adherence\u003c/p\u003e\n\u003cp\u003eMMAS1: Do you ever forget to use sodium hyaluronate 0.4% eyedrop?, MMAS2: Some people forget to take sodium hyaluronate 0.4% eyedrop for reasons other than simple forgetfulness. If you remember from the last 2 weeks, was there a day when you forgot to use sodium hyaluronate 0.4% eyedrop?, MMAS3: Have you ever reduced the dose or stopped using sodium hyaluronate 0.4% eyedrop without telling your doctor because you felt worse when using it?, MMAS4: When you travel or are away from home, do you ever forget to take sodium hyaluronate 0.4% eyedrop?, MMAS5: Did you use sodium hyaluronate 0.4% eyedrop yesterday?, MMAS6: When you feel your eye is better, do you sometimes stop using sodium hyaluronate 0.4% eyedrop?, MMAS7: Using products or medicines every day can be a problem for many people. Do you ever feel pressured to keep up with your treatment for your problem?, MMAS8: How often do you have difficulty remembering to take all your medicines?\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/d13348af218d411d268cec15.png"},{"id":93638588,"identity":"27b8f336-bc4f-4448-b469-d752423940b4","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":102328,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between treatment adherence, knowledge of the product, and educational level.\u003c/p\u003e\n\u003cp\u003eA. Correlation between product knowledge, measured by the number of correct answers, and treatment adherence.\u003c/p\u003e\n\u003cp\u003eB. Correlation between education (1: unfinished elementary school, 2: elementary, 3: middle school, 4: high school, 5: higher education) and treatment adherence\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/081a125f91ac2af051ff8fef.png"},{"id":93638594,"identity":"4b5a9ef9-65eb-4b93-b459-29ecd5a012b4","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":106307,"visible":true,"origin":"","legend":"\u003cp\u003ePatient knowledge of the treatment.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/60a5d642dec2feb5740a3c4b.png"},{"id":93639867,"identity":"ca6818bc-0ae2-4d3d-ae1e-270bd58e0260","added_by":"auto","created_at":"2025-10-16 02:22:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":993338,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/da5fad51-389c-4ef8-a687-82ed0b0a40ac.pdf"},{"id":93639270,"identity":"3e245305-43e6-4af2-a24c-e40cf054f35f","added_by":"auto","created_at":"2025-10-16 02:06:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20544,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial1..docx","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/d287702912ef655b1b813533.docx"},{"id":93638595,"identity":"ec500beb-ba64-4268-a353-231863283209","added_by":"auto","created_at":"2025-10-16 01:58:36","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":285511,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7704248/v1/e821166fdc8c769e0cb63332.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Active surveillance of sodium hyaluronate 0.4% eyedrop: patient knowledge, adherence, and safety findings in real-world use","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eArtificial tears, commonly available as over-the-counter products, are the preferred treatment for dry eye disease. The solutions are typically hypo or isotonic and contain a combination of viscous agents, surfactants, and electrolytes, with or without preservatives.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The composition of artificial tears is compatible with maintaining normal ocular surface epithelium, thus improving the symptoms associated with tear instability.\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eSodium hyaluronate, a glycosaminoglycan abundant in synovial fluid and vitreous humor, is one of the most commonly used viscous agents in artificial tears. Due to its chemical properties, sodium hyaluronate can effectively retain water, thereby providing lubrication to the ocular surface.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Its low toxicity, non-immunogenicity, and lack of genotoxicity contribute to its safety in various ophthalmic formulations.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Furthermore, experimental studies have demonstrated that sodium hyaluronate does not alter the normal conjunctival epithelium, interfere with the secretion processes of goblet cells, or damage the intercellular junctions, in contrast to other artificial tears solutions.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAlthough sodium hyaluronate is considered secure, it is essential to gather longitudinal data to corroborate its long-term safety further. \u003csup\u003e8\u003c/sup\u003e Ongoing safety evaluation, conducted through pharmacovigilance, relies on both active and passive surveillance methods. Passive surveillance serves as the foundation of pharmacovigilance, but it is mainly dependent on the voluntary reporting of adverse events (AEs), which is often less prevalent in ophthalmology compared to other medical specialties. \u003csup\u003e9,10 11\u003c/sup\u003e Therefore, active surveillance methods, such as post-authorization safety studies,\u003csup\u003e8\u003c/sup\u003e are frequently employed.\u003c/p\u003e\u003cp\u003ePASS includes both clinical trials and observational studies. Observational studies are particularly valuable in identifying, quantifying, and characterizing safety risks (such as AEs, product misuse due to insufficient knowledge, and issues related to treatment adherence), thereby complementing the safety profile and assessing the effectiveness of risk minimization measures.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eTo date, there is limited information regarding the use of 0.4% sodium hyaluronate in an uncontrolled population. Therefore, our study presents the findings of an uncontrolled post-authorization safety study of 0.4% sodium hyaluronate, focusing on treatment adherence, user knowledge of the product, and AEs.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Study design.\u003c/h2\u003e\u003cp\u003eWe conducted a prospective, single-center, uncontrolled observational post-authorization study that involved an initial in-person visit (day 0) and three follow-up phone calls (days 5, 15, and 30).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Study population\u003c/h2\u003e\u003cp\u003eThis study included patients over 18 years or older who were prescribed sodium hyaluronate 0.4% for the first time as a new indication and attended the ophthalmology service at the \"Hospital Civil de Guadalajara, Fray Antonio Alcalde,\u0026rdquo; in Guadalajara, M\u0026eacute;xico.\"\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Data collection\u003c/h2\u003e\u003cp\u003ePatients were invited to participate in the study after an ophthalmologist diagnosed them with dry eye and deemed treatment necessary. They were prescribed 0.4% sodium hyaluronate eye drops in a dosage tailored to each patient's specific needs. After obtaining informed consent, the patient's telephone number and medical history were recorded during the initial visit. Subsequently, 5\u0026thinsp;\u0026plusmn;\u0026thinsp;2 days after the initial visit, sociodemographic and AEs were inquired (first call). At 15\u0026thinsp;\u0026plusmn;\u0026thinsp;2 days, only the verification of AE was conducted (second call). Finally, 30\u0026thinsp;\u0026plusmn;\u0026thinsp;2 days later, in addition to verifying AEs, the Morisky Green 8-item survey and the patient's knowledge of the study product were applied (third call). The data were collected between November 2023 to September 2024.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Outcome Variables\u003c/h2\u003e\u003cp\u003eThe primary outcomes of this study included both surveys: patients' knowledge of the study product and treatment adherence, using the 8-item Morisky Medication Adherence Scale (MMAS-8). These outcomes were selected to explore cognitive and behavioral factors that may influence treatment use in clinical practice and patient participation. Secondary outcomes included the incidence, severity, seriousness and causality of AEs reported during follow-up.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Categorization\u003c/h2\u003e\u003cp\u003eThe patient population was classified into two age groups: adults (18\u0026ndash;64 years) and elderly (65 years and older). The level of education was categorized as follows: unfinished elementary school, elementary (grades 1 to 6), middle school (grades 7 to 10), high school (grades 10 to 12), and higher education (bachelor\u0026acute;s degree, master\u0026acute;s degree, or PhD).\u003c/p\u003e\u003cp\u003eIn turn, the severity of the ADRs was assessed using the ADR Severity Assessment Scale (Modified Hartwig and Siegel).\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Subsequently, the ADRs' causal relationships were evaluated per the Naranjo algorithm (Definite, Probable, Possible, Doubtful, and Not Assessable).\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e All ADRs were listed according to MedDRA v27.1 (Medical Dictionary for Regulatory Activities). Finally, seriousness (serious / non-serious) was evaluated by its likeliness to cause permanent damage, life-threatening, or death, according to the International Conference on Harmonisation (ICH).\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6. Patient knowledge of the treatment\u003c/h2\u003e\u003cp\u003ePatient knowledge about the product will be assessed using the questionnaire by \u003cem\u003eGarc\u0026iacute;a-Delgado et al\u003c/em\u003e., which consists of 11 questions, each of which evaluates an essential aspect of the points mentioned below: indication, dose, posology, treatment duration, administration, precaution, AEs, contraindications, effectiveness, interactions and conservation.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Once the survey data is obtained, the interviewer categorizes the responses regarding the Summary of Product Characteristics (SmPC) into three categories: correct, incorrect, and don\u0026rsquo;t know.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.7. Morisky Green (MMAS) test\u003c/h2\u003e\u003cp\u003eAn adapted version of the Morisky Medication Adherence Scale for use in the Spanish population will be utilized to evaluate medication adherence. This assessment consists of eight items that require a dichotomous yes/no response, reflecting the patient's behavior regarding compliance. This test aims to determine whether the patient demonstrates appropriate attitudes toward their treatment. It is assumed that patients with incorrect attitudes may be non-compliant with their prescribed treatment (\u0026le;\u0026thinsp;5 low adherence, 6 to 7 moderate adherence and \u0026gt;\u0026thinsp;8 high adherence).\u003csup\u003e\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e2.8. Statistical analyses\u003c/h2\u003e\u003cp\u003eAll data were evaluated using exploratory data analysis, which encompassed descriptive statistics. This included frequency distributions presented in tables, diagrams, and histograms. The results were displayed through both qualitative and quantitative descriptions, utilizing measures such as the mean (\u0026plusmn;\u0026thinsp;SD) for numerical data and frequencies with percentages for categorical data.\u003c/p\u003e\u003cp\u003eFor the comparison among schooling, patient knowledge, and adherence, statistical methods were selected based on the distribution and scale of the variables as follows:\u003c/p\u003e\u003cp\u003eSince normality was not achieved according to the Shapiro-Wilk test (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), non-parametric methods were employed. When categorical variables were compared with ordinal or discrete variables, the Kruskal-Wallis test was used. If significant differences were identified, post hoc analyses were conducted using Dunn\u0026rsquo;s test with Bonferroni correction to control for Type I error in multiple comparisons.\u003c/p\u003e\u003cp\u003eWhen both variables were categorical, associations were assessed using the chi-square test of independence. For significant chi-square results, post hoc examinations of standardized adjusted residuals were conducted to identify specific contributions, using Bonferroni-adjusted p-values to account for multiple testing. All analyses were performed using RStudio (version 2024.12.0), with significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Baseline and demographic characteristics.\u003c/h2\u003e\u003cp\u003eTwo hundred sixty-one subjects were recruited, with 10% of losses (3 screening failures and 23 losses to follow-up), a total of 235 subjects were completed (154 females and 81 males). The average age of the finished subjects was 53.99\u0026thinsp;\u0026plusmn;\u0026thinsp;18.78 (adult n\u0026thinsp;=\u0026thinsp;151, 64% and elderly n\u0026thinsp;=\u0026thinsp;84, 46%). An 18-week pregnant woman was included in the study. No breastfeeding subjects were enrolled.\u003c/p\u003e\u003cp\u003eThe educational levels of the study subjects were as follows: unfinished elementary (n\u0026thinsp;=\u0026thinsp;36; 15%), elementary (n\u0026thinsp;=\u0026thinsp;57; 24%), middle school (n\u0026thinsp;=\u0026thinsp;37; 16%), high school (n\u0026thinsp;=\u0026thinsp;57; 24%), and superior grades (n\u0026thinsp;=\u0026thinsp;48; 21%).\u003c/p\u003e\u003cp\u003eThe highest incidence of comorbidities in the study were: hypertension (n\u0026thinsp;=\u0026thinsp;55), diabetes (n\u0026thinsp;=\u0026thinsp;46), cataracts (n\u0026thinsp;=\u0026thinsp;11), hypothyroidism (n\u0026thinsp;=\u0026thinsp;8) and rheumatoid arthritis (n\u0026thinsp;=\u0026thinsp;7). Regarding concomitant medications, the most frequent were hypoglycemic agents, such as metformin (n\u0026thinsp;=\u0026thinsp;40) and insulin (n\u0026thinsp;=\u0026thinsp;31), followed by antihypertensives, including losartan (n\u0026thinsp;=\u0026thinsp;26), telmisartan (n\u0026thinsp;=\u0026thinsp;12), amlodipine (n\u0026thinsp;=\u0026thinsp;6), and enalapril (n\u0026thinsp;=\u0026thinsp;6); finally, the synthetic hormone levothyroxine (n\u0026thinsp;=\u0026thinsp;11).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Morisky Green (MMAS) test\u003c/h2\u003e\u003cp\u003eIn the Morisky Green test, it was observed that most of the study subjects obtained a score of moderate adherences (44%) followed by high (32%) and finally low (24%). A detailed analysis of the data showed that 49% of the patients forgot to use the product at some point during the treatment (MMAS1) and 32% of the subjects forgot to use the product at least once in the 2 weeks before the survey (MMAS2); on the contrary, only 1% of the respondents feel pressured to continue the treatment for their problem (MMAS7) or have reduced the dose or stopped using the product without telling their doctor because they felt worse when using the product (MMAS3) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFurthermore, the data indicated a direct relationship between product education level and treatment adherence, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB. Participants who answered more questions correctly tended to have higher adherence rates, which was also correlated with an increased level of education among the subjects.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eA chi-square test was conducted to evaluate the association between educational level and treatment adherence. The results revealed a statistically significant association (χ\u0026sup2;(df\u0026thinsp;=\u0026thinsp;8)\u0026thinsp;=\u0026thinsp;22.659, p\u0026thinsp;=\u0026thinsp;0.00383). Post hoc analysis based on standardized adjusted residuals revealed a significant overrepresentation in the unfinished elementary school and low adherence group (p\u0026thinsp;=\u0026thinsp;0.0056) and a trend toward higher education and high adherence\" combination (p\u0026thinsp;=\u0026thinsp;0.0546) (Supplementary material 1).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.3. Patient knowledge of the treatment.\u003c/h2\u003e\u003cp\u003eThe participants achieved a median score of 7 out of 10 on the product knowledge questionnaire, with scores ranging between 5 and 10.\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e illustrates the subjects' knowledge across the various sections outlined in the methodology. Notably, 100% of participants answered correctly regarding the product's \"dose\" and \"posology.\" In contrast, knowledge related to \"interactions\" (0%), \"AEs\" (9%), and \"contraindications\u0026rdquo; (10%) had the lowest response rate, indicating that these areas were the least understood by the subjects. Similar to the association between education level and treatment adherence, there is also a correlation between product knowledge, education level, and treatment adherence (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eA Kruskal-Wallis test was performed to examine differences in product knowledge across educational levels. The test showed a highly significant effect (H(df\u0026thinsp;=\u0026thinsp;4)\u0026thinsp;=\u0026thinsp;24.038, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Post hoc comparisons revealed significant differences between \"Higher education\" and \"Elementary\" (p\u0026thinsp;=\u0026thinsp;0.003) and between \"Higher education\" and \"Middle school\" (p\u0026thinsp;=\u0026thinsp;0.0088). The comparison between \"Higher education\" and \"Unfinished elementary school\" showed a suggestive trend (p\u0026thinsp;=\u0026thinsp;0.036) but was not statistically significant. This indicates that the higher the educational level, the greater the knowledge about the product.\u003c/p\u003e\u003cp\u003eBesides, the Kruskal-Wallis test examining the relationship between product knowledge and adherence also showed statistically significant differences (H(df\u0026thinsp;=\u0026thinsp;2)\u0026thinsp;=\u0026thinsp;12.512, p\u0026thinsp;=\u0026thinsp;0.002). Dunn's post hoc analysis revealed significant differences between the \"High knowledge \u0026ndash; Low adherence\" group (p\u0026thinsp;=\u0026thinsp;0.050) and the \"High knowledge \u0026ndash; Medium adherence\" group (p\u0026thinsp;=\u0026thinsp;0.008), indicating that increased product knowledge was associated with improved adherence (Supplementary material 1).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.4. Adverse events\u003c/h2\u003e\u003cp\u003eOf the two hundred sixty-one patients, only 7 (8 EAs), representing less than 3% of the total participants. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e outlines the characteristics of these subjects. The average age of the participants was 54.9 years\u0026thinsp;\u0026plusmn;\u0026thinsp;19.0, and the majority were female (63%). The most frequently reported system organ class (SOC) was ocular disorders, occurring in 63% of cases, with the preferred term (PT) of eye irritation affecting 25% of subjects. Most cases were classified as mild and not serious (88%), with only one considered serious. The causality was assessed as possible in 63% of the cases. Additionally, the PTs nasal congestion, eye pruritus, and dry eye were categorized as unexpected events.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, a strong relationship was observed between patients\u0026rsquo; product knowledge and their treatment adherence, as reflected in the adherence scores and educational background of the participants. Several studies support the notion that patient empowerment and awareness regarding their medication, as well as socioeconomic status, significantly influence the disease management of their condition.\u003csup\u003e\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Moreover, our results indicate that educational level plays a crucial role in adherence, a finding consistent with previous reports that have linked low educational attainment to poor treatment compliance.\u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003eNonetheless, Okuno et al. and Yavuz et al., mention that additional factors influencing, including cognitive impairment, limited communication with healthcare professionals, low perception of treatment benefit, poor motivation, socioeconomic constraints, and lack of social or familial support.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAs previously mentioned, our findings revealed an association between educational attainment and treatment adherence, with notably lower adherence among participants with unfinished elementary education (p\u0026thinsp;=\u0026thinsp;0.0056). In comparison, higher education levels tended to correlate with better adherence. Furthermore, product knowledge was significantly higher among participants with higher education (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and this knowledge was positively associated with adherence (p\u0026thinsp;=\u0026thinsp;0.002). These relationships are particularly relevant when interpreted in conjunction with the pharmacovigilance data.\u003c/p\u003e\u003cp\u003eDespite specifically screening patients for AEs, the pharmacovigilance data revealed notably low rates (\u0026lt;\u0026thinsp;3%). This rate is considerably lower than that observed in other studies utilizing sodium hyaluronate formulations. \u003csup\u003e1,28\u003c/sup\u003e The low incidence of AEs may initially appear favorable, but it could reflect an underestimation influenced by participants' limited awareness of risks, this is consistent with our findings that indicated where only 9% of patients were aware of adverse drug reactions.\u003c/p\u003e\u003cp\u003eThe significantly lower adherence observed among individuals with unfinished elementary education likely reflects structural barriers such as low health literacy, limited access to information, and socioeconomic disadvantage, factors widely documented as contributors to poor adherence.\u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Besides, participants with higher education demonstrated greater knowledge about the product and a corresponding increase in adherence, supporting the well-established link between patient education and treatment engagement. The results suggest that poor adherence and underreporting may share a common origin. These insights underscore the clinical significance of implementing targeted educational strategies, particularly in vulnerable populations, not only to enhance adherence but also to improve the accuracy of safety data collection and promote patient empowerment in therapeutic decision-making.\u003c/p\u003e\u003cp\u003eRegarding the reported AEs, ocular irritation was classified as infrequent according to the CIOMS classification, whereas the product monograph lists it as a frequent adverse reaction.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Furthermore, blurred vision, commonly reported with artificial tears, was not observed in any case. The disparity between expected and observed AEs suggests underreporting, which is likely due to patients' limited knowledge and recognition of potential adverse effects. This phenomenon is consistent with previous findings indicating that inadequate understanding contributes to the underreporting of AEs in pharmacovigilance.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn addition, three were classified as unexpected: nasal congestion, ocular itching, and dry eye; however, the causality was low (doubtful and possible). No references in the literature or the product\u0026rsquo;s Summary of Product Characteristics (SmPC) associate sodium hyaluronate or artificial tears with nasal congestion or eye pruritus, \u003csup\u003e32\u0026ndash;37\u003c/sup\u003e which could indicate that there is no causal relationship between the event and the drug. However, these reports may also reflect limited patient awareness of expected adverse effects, potentially leading to misattribution or overreporting of unrelated symptoms.\u003c/p\u003e\u003cp\u003eAbout dry eye, this condition indicates a lack of therapeutic effectiveness rather than a side effect of the treatment. The product, which is not approved for use in patients with severe dry eye, may not be sufficient to alleviate symptoms in specific individuals. Although various authors mention tachyphylaxis, such as therapeutic inefficacy or lack of efficacy,\u003csup\u003e38\u0026ndash;40\u003c/sup\u003e most SmPCs do not list ineffectiveness as an adverse drug reaction. This is particularly true when pharmacological action is present but insufficient due to the progression or severity of the disease. For example, it would be inappropriate to label an NSAID as ineffective in patients requiring opioids for severe pain, or to classify a hypoglycemic agent as ineffective in cases where disease advancement necessitates insulin. Similarly, the absence of a clinical response to sodium hyaluronate in certain patients may reflect a limitation in therapeutic scope rather than an unexpected safety concern.\u003c/p\u003e"},{"header":"5. Limitations of the Study","content":"\u003cp\u003eThis study has some limitations. The use of structured surveys to assess knowledge and adherence may be subject to recall or response bias. Despite this, the findings highlight the importance of patient education in improving adherence and the quality of pharmacovigilance data.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eThe present study provides valuable information on patient behavior and pharmacovigilance related to 0.4% sodium hyaluronate eye drops. A strong and consistent association was found between educational level, product knowledge, and treatment adherence, underscoring the vital role of health literacy in achieving optimal therapeutic outcomes. The findings emphasize the need to integrate patient education strategies to improve therapeutic adherence and ensure safe medication use, particularly for self-administered ophthalmic treatments. Although the reported incidence of AEs was lower than that indicated in the SmPC for similar products, this may reflect underreporting due to a lack of patient awareness rather than a genuinely lower incidence. Overall, this study emphasizes the importance of active surveillance methods that not only monitor AEs but also investigate patient-level factors affecting real-world medication use.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data is available upon request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study and the informed consent process were approved by the Investigation Committee (Approval number CI-1381/22) and the Research Ethics Committee (Approval number CEI-1378/22) of the Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde, located in Guadalajara, Mexico. All participants were given a comprehensive explanation of the study and provided written informed consent. The present study was conducted in accordance with the standards of the Declaration of Helsinki, the Nuremberg Code, the Belmont Report, and the International Ethical Guidelines for Epidemiological Studies of the Council for International Organizations of Medical Sciences (CIOMS).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLaboratorios Sophia, S.A. de C.V. provided salary support for authors H. C-S, J.C.V-B, and L.Y. R-H, but did not have any additional role in the data collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was sponsored by Laboratorios Sophia, S.A. de C.V. (Zapopan, Jalisco, M\u0026eacute;xico).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Dr. Sarahi del Carmen Gomez Macias for her assistance writing the medical manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCopyright\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUS Copyright laws protect the use of the \u0026copy;MMAS. The authors have obtained permission to use the 8-item Morisky Medication Adherence Scale (Supplementary material 2).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eContreras-Salinas H, Barajas-Hern\u0026aacute;ndez M, Baiza-Dur\u0026aacute;n LM, Orozco-Ceja V, Rodr\u0026iacute;guez-Herrera LY. Ophthalmic solution safety profile: Active surveillance of a sodium hyaluronate/chondroitin sulfate combination in peruvian population. Drug Healthc Patient Saf. 2021;13:117\u0026ndash;23. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/DHPS.S311817\u003c/span\u003e\u003cspan address=\"10.2147/DHPS.S311817\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePhadatare SP, Momin M, Nighojkar P, Askarkar S, Singh KK. A Comprehensive Review on Dry Eye Disease: Diagnosis, Medical Management, Recent Developments, and Future Challenges. Adv Pharm. 2015;2015(1):704946. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2015/704946\u003c/span\u003e\u003cspan address=\"10.1155/2015/704946\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCraig JP, Nelson JD, Azar DT, et al. TFOS DEWS II Report Executive Summary. Ocul Surf. 2017;15(4):802\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jtos.2017.08.003\u003c/span\u003e\u003cspan address=\"10.1016/j.jtos.2017.08.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAragona P, Papa V, Micali A, Santocono M, Milazzo G. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol. 2002;86(2):181\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bjo.86.2.181\u003c/span\u003e\u003cspan address=\"10.1136/bjo.86.2.181\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShimmura S, Ono M, Shinozaki K, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol. 1995;79(11):1007\u0026ndash;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bjo.79.11.1007\u003c/span\u003e\u003cspan address=\"10.1136/bjo.79.11.1007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBecker LC, Bergfeld WF, Belsito DV, et al. Final Report of the Safety Assessment of Hyaluronic Acid, Potassium Hyaluronate, and Sodium Hyaluronate. Int J Toxicol. 2009;28(4suppl):5\u0026ndash;67. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/1091581809337738\u003c/span\u003e\u003cspan address=\"10.1177/1091581809337738\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAragona P, Di Stefano G, Ferreri F, Spinella R, Stilo A. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sj\u0026ouml;gren\u0026rsquo;s syndrome patients. Br J Ophthalmol. 2002;86(8):879\u0026ndash;84. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bjo.86.8.879\u003c/span\u003e\u003cspan address=\"10.1136/bjo.86.8.879\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLucas S, Ailani J, Smith TR, Abdrabboh A, Xue F, Navetta MS. Pharmacovigilance: reporting requirements throughout a product\u0026rsquo;s lifecycle. Ther Adv drug Saf. 2022;13:20420986221125010. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/20420986221125006\u003c/span\u003e\u003cspan address=\"10.1177/20420986221125006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMwakawanga DL, Kilonzi M, Philipo EG, et al. Pharmacovigilance and Adverse Drug Reactions Reporting: Healthcare Providers\u0026rsquo; Experiences from Southern Highland Tanzania. Adv Pharmacol Pharm Sci. 2023;2023:5537592. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2023/5537592\u003c/span\u003e\u003cspan address=\"10.1155/2023/5537592\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLomeli-Silva A, Contreras-Salinas H, Barajas-Virgen MY, Romero-Lopez MS, Rodr\u0026iacute;guez-Herrera LY. Harmonization of individual case safety reports transmission requirements among PAHO reference authorities: a review of their current regulation. Ther Adv Drug Saf. 2024;15:20420986241228120. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/20420986241228119\u003c/span\u003e\u003cspan address=\"10.1177/20420986241228119\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eContreras-Salinas H, Baiza-Dur\u0026aacute;n LM, Bautista-Castro MA, Alonso-Rodr\u0026iacute;guez DR, Rodr\u0026iacute;guez-Herrera LY. Underreporting and Triggering Factors for Reporting ADRs of Two Ophthalmic Drugs: A Comparison between Spontaneous Reports and Active Pharmacovigilance Databases. Healthc (Basel Switzerland). 2022;10(11). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/healthcare10112182\u003c/span\u003e\u003cspan address=\"10.3390/healthcare10112182\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEuropean Medicines Agency (EMA). Post-authorisation safety studies (PASS). Accessed August 20. 2024. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/post-authorisation-safety-studies-pass\u003c/span\u003e\u003cspan address=\"https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/post-authorisation-safety-studies-pass\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm. 1992;49(9):2229\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePetrova G, Stoimenova A, Dimitrova M, Kamusheva M, Petrova D, Georgiev O. Assessment of the expectancy, seriousness and severity of adverse drug reactions reported for chronic obstructive pulmonary disease therapy. SAGE open Med. 2017;5:2050312117690404. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/2050312117690404\u003c/span\u003e\u003cspan address=\"10.1177/2050312117690404\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNaranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239\u0026ndash;45. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/clpt.1981.154\u003c/span\u003e\u003cspan address=\"10.1038/clpt.1981.154\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eInternational Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH). Maintenance of the ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports E2B (R2). 2001. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://admin.ich.org/sites/default/files/inline-files/E2B_R2_Guideline.pdf\u003c/span\u003e\u003cspan address=\"https://admin.ich.org/sites/default/files/inline-files/E2B_R2_Guideline.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a Delgado P, Gastelurrutia Garralda MA, Baena Parejo MI, Fisac Lozano F, Mart\u0026iacute;nez Mart\u0026iacute;nez F. [Validation of a questionnaire to assess patient knowledge of their medicines]. Aten primaria. 2009;41(12):661\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.aprim.2009.03.011\u003c/span\u003e\u003cspan address=\"10.1016/j.aprim.2009.03.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartinez-Perez P, Orozco-Beltr\u0026aacute;n D, Pomares-Gomez F, et al. Validation and psychometric properties of the 8-item Morisky Medication Adherence Scale (MMAS-8) in type 2 diabetes patients in Spain. Atenci\u0026oacute;n Primaria. 2021;53(2). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.aprim.2020.09.007\u003c/span\u003e\u003cspan address=\"10.1016/j.aprim.2020.09.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMedina-Rodr\u0026iacute;guez JC, Lugo-Bautista KS, Consistency. Reliability, and Validation of the 8-Item Morisky Medication Adherence Scale in Mexican Patients with Depressive Disorders and Type 2 Diabetes Mellitus. Rev la Asoc Psiquiatr Mex. 2024;4(2):27\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKrousel-Wood M, Islam T, Webber LS, Re RN, Morisky DE, Muntner P. New medication adherence scale versus pharmacy fill rates in seniors with hypertension. Am J Manag Care. 2009;15(1):59\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTaibanguay N, Chaiamnuay S, Asavatanabodee P, Narongroeknawin P. Effect of patient education on medication adherence of patients with rheumatoid arthritis: a randomized controlled trial. Patient Prefer Adherence. 2019;13:119\u0026ndash;29. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/PPA.S192008\u003c/span\u003e\u003cspan address=\"10.2147/PPA.S192008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJin J, Sklar GE, Min Sen Oh V, Chuen Li S. Factors affecting therapeutic compliance: A review from the patient\u0026rsquo;s perspective. Ther Clin Risk Manag. 2008;4(1):269\u0026ndash;86. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/tcrm.s1458\u003c/span\u003e\u003cspan address=\"10.2147/tcrm.s1458\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThummak S, Uppor W, Wannarit LO. Patient compliance: A concept analysis. Belitung Nurs J. 2023;9(5):421\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.33546/bnj.2807\u003c/span\u003e\u003cspan address=\"10.33546/bnj.2807\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eApter AJ, Boston RC, George M, et al. Modifiable barriers to adherence to inhaled steroids among adults with asthma: it\u0026rsquo;s not just black and white. J Allergy Clin Immunol. 2003;111(6):1219\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1067/mai.2003.1479\u003c/span\u003e\u003cspan address=\"10.1067/mai.2003.1479\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOkuno J, Yanagi H, Tomura S. Is cognitive impairment a risk factor for poor compliance among Japanese elderly in the community? Eur J Clin Pharmacol. 2001;57(8):589\u0026ndash;94. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s002280100347\u003c/span\u003e\u003cspan address=\"10.1007/s002280100347\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGhods AJ, Nasrollahzadeh D. Noncompliance with immunnosuppressive medications after renal transplantation. Exp Clin Transpl Off J Middle East Soc Organ Transpl. 2003;1(1):39\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYavuz A, Tuncer M, Erdoğan O et al. Is there any effect of compliance on clinical parameters of renal transplant recipients? \u003cem\u003eTransplant Proc\u003c/em\u003e. 2004;36(1):120\u0026ndash;121. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.transproceed.2003.11.052\u003c/span\u003e\u003cspan address=\"10.1016/j.transproceed.2003.11.052\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBelalc\u0026aacute;zar-Rey S, S\u0026aacute;nchez Huerta V, Ochoa-Tabares JC, et al. Efficacy and Safety of Sodium Hyaluronate/chondroitin Sulfate Preservative-free Ophthalmic Solution in the Treatment of Dry Eye: A Clinical Trial. Curr Eye Res. 2021;46(7):919\u0026ndash;29. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/02713683.2020.1849733\u003c/span\u003e\u003cspan address=\"10.1080/02713683.2020.1849733\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Laboratorios Sophia SA. C.V. \u003cem\u003eMonograf\u0026iacute;a Lagricel Ofteno\u003c/em\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCosta C, Abeijon P, Rodrigues DA, Figueiras A, Herdeiro MT, Torre C. Factors associated with underreporting of adverse drug reactions by patients: a systematic review. Int J Clin Pharm. 2023;45(6):1349\u0026ndash;58. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11096-023-01592-y\u003c/span\u003e\u003cspan address=\"10.1007/s11096-023-01592-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMatos C, van Hunsel F, Joaquim J. Are consumers ready to take part in the Pharmacovigilance System?--a Portuguese preliminary study concerning ADR reporting. Eur J Clin Pharmacol. 2015;71(7):883\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00228-015-1867-2\u003c/span\u003e\u003cspan address=\"10.1007/s00228-015-1867-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBausch. \u0026amp; Lomb. Minims Artificial Tears, Eye drops solution. 2018. Accessed January 28, 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.medicines.org.uk/emc/product/3737/smpc/print\u003c/span\u003e\u003cspan address=\"https://www.medicines.org.uk/emc/product/3737/smpc/print\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAvKARE, ARTIFICIAL TEARS- artificial tears solution/ drops. 2024. Accessed January 28, 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f18bebf2-1936-658f-e053-2a95a90a5012\u003c/span\u003e\u003cspan address=\"https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f18bebf2-1936-658f-e053-2a95a90a5012\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVizulize. VIZhyal 0.4% Product Information. 2019. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.vizulize.com/wp-content/uploads/2019/07/VIZhyal-0.4-product-information-1.pdf\u003c/span\u003e\u003cspan address=\"https://www.vizulize.com/wp-content/uploads/2019/07/VIZhyal-0.4-product-information-1.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePharma Stulln GmbH. Hylan 0,15/0,15 mg/ml. 2015. Accessed January 26, 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.geneesmiddeleninformatiebank.nl/smpc/h115288_smpc.pdf\u003c/span\u003e\u003cspan address=\"https://www.geneesmiddeleninformatiebank.nl/smpc/h115288_smpc.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eURSAPHARM Arzneimittel GmbH, HYCOSAN\u0026reg; EXTRA., Accessed. January 25, 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://dryeyes.help/wp-content/uploads/2021/01/Hycosan-Extra-Patient-Information-Leaflet.pdf\u003c/span\u003e\u003cspan address=\"https://dryeyes.help/wp-content/uploads/2021/01/Hycosan-Extra-Patient-Information-Leaflet.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTRB CHEMEDICA. Summary of product characteristics VISMED\u0026reg; MULTI. 2017. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://trbchemedica.co.uk/blogs/dry-eye-product-smpcs/vismed-multi-smpc\u003c/span\u003e\u003cspan address=\"https://trbchemedica.co.uk/blogs/dry-eye-product-smpcs/vismed-multi-smpc\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeyboom RH, Lindquist M, Flygare AK, Biriell C, Edwards IR. The value of reporting therapeutic ineffectiveness as an adverse drug reaction. Drug Saf. 2000;23(2):95\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2165/00002018-200023020-00001\u003c/span\u003e\u003cspan address=\"10.2165/00002018-200023020-00001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFigueras A, Pedr\u0026oacute;s C, Valsecia M, Laporte JR. Therapeutic Ineffectiveness. Drug Saf. 2002;25(7):485\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2165/00002018-200225070-00002\u003c/span\u003e\u003cspan address=\"10.2165/00002018-200225070-00002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFranceschi A, Tuccori M, Bocci G, et al. Drug therapeutic failures in emergency department patients. A university hospital experience. Pharmacol Res. 2004;49(1):85\u0026ndash;91. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.phrs.2003.08.001\u003c/span\u003e\u003cspan address=\"10.1016/j.phrs.2003.08.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Adverse events\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (Yeas)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePosology\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcomitants\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEvent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCausality\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExpectedness\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeverity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeriousness\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 34px;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 23px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 44px;\"\u003e\n \u003cp\u003e1 drop each 4h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 69px;\"\u003e\n \u003cp\u003eRheumatoid arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eVitamin D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eNasal congestion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eNasal congestion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eDoubtful\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eItchy ears\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eEar pruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003eEar and labyrinth disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"7\" style=\"width: 34px;\"\u003e\n \u003cp\u003e74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 23px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 44px;\"\u003e\n \u003cp\u003e1 drop each 4h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 69px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eAmlodipine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 57px;\"\u003e\n \u003cp\u003eOcular irritation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 69px;\"\u003e\n \u003cp\u003eEye irritation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 73px;\"\u003e\n \u003cp\u003eEye disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 47px;\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 63px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 41px;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"7\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eLosartan\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eAtorvastatin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eDapagliflozin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eMetoprolol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePropafenone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eMetformin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e1 drop each 4h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eOcular pruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eEye pruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003eEye disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 34px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 23px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 44px;\"\u003e\n \u003cp\u003e1 drop each 12h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 69px;\"\u003e\n \u003cp\u003eChronic kidney disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePrednisone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 57px;\"\u003e\n \u003cp\u003eOcular irritation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 69px;\"\u003e\n \u003cp\u003eEye irritation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 73px;\"\u003e\n \u003cp\u003eEye disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 47px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 63px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 41px;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eApixaban\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eTacrolimus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eMycophenolic Acid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eNitrofurantoin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e1 drop each 4h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eCataract surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eDry eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eDry eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003eEye disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44px;\"\u003e\n \u003cp\u003e1 drop each 4h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eDysautonomia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eAllergic reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eHypersensitivity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003eImmune system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 63px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 34px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 23px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 44px;\"\u003e\n \u003cp\u003e2 drop each 4h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eCataract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eLosartan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u0026nbsp;Tearing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 69px;\"\u003e\n \u003cp\u003eLacrimation increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 73px;\"\u003e\n \u003cp\u003eEye disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 47px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 63px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 41px;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 69px;\"\u003e\n \u003cp\u003eDiabetes Mellitus II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eMetoprolol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eAtorvastatin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eMetformin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Adverse Event, Artificial Tear, Sodium Hyaluronate, Patient's Knowledge, Morisky Green","lastPublishedDoi":"10.21203/rs.3.rs-7704248/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7704248/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThis study aimed to evaluate the relationship between patient knowledge, educational level, and treatment adherence to sodium hyaluronate 0.4% eyedrops, while also identifying reported adverse events (AEs) in a real-world, post-authorization setting.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eA prospective, single-center, observational study was conducted with patients receiving sodium hyaluronate 0.4%. An initial in-person visit was followed by three follow-up phone calls (days 5, 15, and 30) to identify AEs and complete two questionnaires: the 8-item Morisky Green Medication Adherence Scale (MMAS-8) and the patient's knowledge of the study product.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eAmong 261 enrolled participants, 235 completed follow-ups. A clear association was found between product knowledge, educational level, and treatment adherence. Participants with higher education scored better on the knowledge survey and showed greater adherence. Less than 3% of the participants experienced AEs. The most frequently preferred term (PT) was eye irritation, with most AEs classified as mild and non-serious (88%).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eHealth literacy emerged as a key determinant of adherence to 0.4% sodium hyaluronate eye drops, strongly linked to education and product knowledge. The study emphasizes the importance of patient education and active surveillance in optimizing adherence and ensuring the safe use of self-administered ophthalmic therapies.\u003c/p\u003e","manuscriptTitle":"Active surveillance of sodium hyaluronate 0.4% eyedrop: patient knowledge, adherence, and safety findings in real-world use","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-16 01:58:31","doi":"10.21203/rs.3.rs-7704248/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-12-17T16:06:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"232441215936237716999644980377863938871","date":"2025-12-07T05:37:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-02T13:16:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-02T12:59:35+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-30T07:12:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-29T14:11:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-09-29T14:07:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a3c31ef-951c-4eb3-944e-dff8b9797ae1","owner":[],"postedDate":"October 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-16T01:58:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-16 01:58:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7704248","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7704248","identity":"rs-7704248","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}