Branded Compared with Generic Latanoprost in Glaucoma Therapy: Where Do We Stand?

Abstract

In this literature review, branded and generic preserved latanoprost are compared with respect to comparative efficacy, tolerability, and physicochemical properties. Worldwide, latanoprost, a prostaglandin analogue, has evolved into the first-line medical treatment for patients with open-angle glaucoma or ocular hypertension. Following the launch of multiple latanoprost generic preparations, clinicians and patients face a dilemma between prescribing the original branded product or its more affordable generic counterparts. While, in theory, branded and generic latanoprost formulations share the same active and inactive ingredients, available studies comparing their efficacy have reported conflicting results. Further, published evidence has demonstrated several subtle and sometimes manifest differences in terms of active ingredient content, benzalkonium chloride (BAK) concentration, pH level, osmolality, particulate content, and drop size. Moreover, degradation of the active ingredient under adverse temperature conditions is reportedly more pronounced with generic latanoprost. Recorded differences may negatively affect long-term efficacy, tolerability, ocular surface health, and adherence. However, to what extent these differences play a role in glaucoma care over the long term remains to be determined. Until such information becomes available, latanoprost therapy should be individualized, and careful patient monitoring is recommended. We conclude that stricter regulatory oversight of antiglaucoma eyedrops should be sought to ensure the safety and consistency of action of all available generic formulations.

Key Summary Points

Why carry out this study?

Preserved generic latanoprost preparations offer a significant cost benefit when employed in glaucoma therapy.

In view of their worldwide popularity, it is vital to understand how closely they compare with branded latanoprost.

What was learned from this study?

The present review has critically evaluated available evidence for preserved branded and generic latanoprost.

Available evidence has demonstrated several subtle and sometimes manifest differences between branded and generic latanoprost preparations. Documented differences include active ingredient concentration, benzalkonium chloride content, pH level, osmolality, particulate content, drop size, and degree of degradation under adverse temperature conditions.

To what extent recorded differences influence long-term efficacy, tolerability, ocular surface health, and adherence with generic latanoprost therapy remains to be determined.

Introduction

Prostaglandin analogues (PGAs) are widely regarded as the first-line pharmacological therapy for patients with elevated intraocular pressure (IOP) or glaucoma that merit therapy [1, 2]. PGAs lower IOP, the only modifiable risk factor for glaucoma development and progression, by enhancing aqueous humor outflow by means of two mechanisms [3]. All PGAs bind to the prostaglandin F receptor subtype (FP receptors) located in the ciliary epithelium, muscle, and stroma, resulting in remodeling of the extracellular matrix and increased permeability of the sclera and ciliary muscle, thus increasing uveoscleral (unconventional) outflow [3, 4]. They also interact with E-proteinoid (EP) receptors within the trabecular meshwork, promoting structural remodeling and cellular relaxation, which enhance the conventional outflow pathway [4]. Cumulative evidence suggests that PGAs provide the greatest IOP-lowering efficacy among topical antiglaucoma agents, achieving IOP reductions between 24% and 30%, with a favorable systemic safety profile compared to other therapeutic agents [2, 4, 5]. They do demonstrate, however, a variable rate of topical adverse events, including ocular hyperemia, eyelash growth, iris hyperpigmentation, and, rarely, cystoid macular edema [5–8]. Importantly, their once daily administration, typically at night, is considered to promote patient convenience and adherence [6, 9].

In 1996, latanoprost 0.005% (Xalatan^®, Pharmacia) became the first PGA to be approved by the U.S. Food and Drug Administration (FDA) for lowering IOP in subjects with either open-angle glaucoma or ocular hypertension [10, 11]. Despite the subsequent introduction of newer PGAs, such as bimatoprost 0.03%, which may offer greater efficacy [11–13], latanoprost ophthalmic solution remained the most widely prescribed PGA globally [14–16], predominately due to a more favorable topical tolerability profile. Following the loss of patent protection in 2011, and owing to its popularity in glaucoma therapy worldwide, numerous generic versions of preserved latanoprost 0.005% ophthalmic solution have been launched on the market [6, 17]. For example, currently, there are 8 different latanoprost generics available on the market in Greece, 23 in Germany and 9 in the United States [17–20]. Although there is a marked variation in the number of generic preparations across different countries, there is a strong global presence of latanoprost generics, with market dynamics influencing availability and utilization across different countries. Apart from creating new marketing opportunities for pharmaceutical companies, the introduction of generic latanoprost formulations has significantly improved cost-effectiveness of this first-line glaucoma treatment, with a significant reduction in cost worldwide. Indeed, the reduction in annual cost was reported in the US to be as much as $1014 per patient treated [21]. Conceivably, this cost reduction may also improve adherence in some health systems, since cost of medication is a well-recognized barrier to patients’ adherence with treatment [9, 22].

Oral generic medications must demonstrate bioequivalence to the reference listed drug in order to gain regulatory approval [23]. This requires them to contain the same active ingredient, be administered via the same route and dosage, and be manufactured under equivalent quality and regulatory standards [23–25]. Regulatory bodies such as the FDA and the European Medicines Agency (EMA) require both in vitro and in vivo studies to confirm bioequivalence [24, 25]. In vitro studies assess the physicochemical properties of the generic formulation compared to the reference product, while in vivo studies involve either pharmacokinetic assessments, drug metabolite analysis, or clinical endpoint evaluations [23]. To establish bioequivalence, these formulations must demonstrate similarity in qualitative (Q1: types of active and inactive substances), quantitative (Q2: exact concentrations of these substances), and physicochemical (Q3: properties such as pH, viscosity, osmolality, specific gravity, and buffer capacity) characteristics [23].

For ophthalmic formulations, however, conventional in vivo bioequivalence studies are typically not feasible because the active ingredients are minimally absorbed systemically, and plasma concentrations do not correlate with therapeutic efficacy (Table 1) [23]. Additionally, a key distinction for ophthalmic solutions is that regulatory authorities, such as the FDA, EMA, and WHO, consider bioequivalence to be self-evident when qualitative (Q1) and quantitative (Q2) sameness is proven by an in vitro study with an allowed variability up to ± 10% between the active and inactive ingredients of the generic and reference ophthalmic solution [23, 25]. Consequently, when this criterion is met, in vivo comparative efficacy studies are generally waived, and direct clinical comparisons between generic and reference ophthalmic products are not required by law [24, 25].

Table 1.

Comparison of the required steps for approval of a new branded versus generic ophthalmic solution

Steps for approval	Branded ophthalmic solution	Generic ophthalmic solution
1. Initial development	Drug discovery and early research	Identify reference listed drug
2. Pre-clinical studies	Laboratory and animal testing for safety and efficacy	Not applicable
3. Regulatory filing for human trials	Investigational new drug application (preclinical data, clinical protocols)	Not applicable
4. Clinical trials	In vivo bioequivalence human studies (phases I, II, III) for safety and efficacy	Not applicable
5. Bioequivalence		In vitro bioequivalence studies to declare similarity of active and inactive ingredients
6. Application submission	New drug application submission (results of in vivo trials, manufacturing details)	New drug application submission (results of in vitro trials, dosage form, manufacturing details)
7. Regulatory review and approval	FDA/EMA review and approval	FDA/EMA review and approval
8. Market access	Market access	Market access

It is important to note that this ± 10% variation in the concentration of both active and inactive ingredients allowed under current regulatory guidelines may represent a significant drawback, as even small deviations may influence clinical efficacy. Furthermore, differences in the concentration of active and inactive ingredients (especially in preservative concentration) for latanoprost generics may negatively impact long-term tolerability. Special attention is required for the effects of the commonest preservative employed in ophthalmic formulations including latanoprost, i.e., benzalkonium chloride (BAK). Given these considerations, it is essential to evaluate whether generic versions of latanoprost have the same performance and truly match the reference listed drug in all relevant physicochemical aspects. The present narrative review aims to synthesize clinical and laboratory evidence comparing branded with preserved generic latanoprost, focusing on (1) IOP-lowering efficacy, (2) ocular-surface tolerability, (3) physicochemical/stability characteristics, and (4) practical and regulatory implications.

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Methods

Search Strategy

A comprehensive literature search was performed between February 2025 and September 2025, across PubMed, Google Scholar, and the Cochrane Library, using combinations of free text keywords and Medical Subject Headings (MeSH) terms including ‘Xalatan’, ‘latanoprost preserved generic’, ‘latanoprost preserved branded’, ‘preserved latanoprost tolerability’, ‘preserved latanoprost efficacy’, ‘preserved latanoprost physicochemical properties’. Different combinations of these terms were used to make sure all relevant studies are captured. The search strategy focused on preserved latanoprost ophthalmic solutions. This approach allowed us to identify all the existing studies that compared branded to generic latanoprost ophthalmic solution, including studies that focused on their physical and chemical properties. Studies published until September 2025 were included in this literature review. Moreover, we included studies in any language if an English, French or German abstract or translation was available.

Inclusion and Exclusion Criteria

We included both prospective randomized controlled trials and retrospective studies that evaluated the efficacy and tolerability of branded versus generic preserved latanoprost ophthalmic solution. We particularly sought crossover studies directly comparing branded and generic latanoprost preparations. Studies without accessible full-text manuscripts or abstracts were excluded from our analyses along with case reports and editorials.

Results

Comparing the Efficacy of Branded Versus Generic Latanoprost

Branded latanoprost was marketed as a sterile, isotonic, buffered aqueous solution containing 50 µg of latanoprost per milliliter [26]. Each drop of the solution delivers approximately 1.5 µg of latanoprost [26]. Prior research has demonstrated that latanoprost has a binding affinity for EP1, and EP3 prostaglandin receptors, and a marked preference and higher selectivity for the FP receptor subtype [4]. Therefore, it affects mostly the unconventional aqueous outflow with IOP lowering becoming manifest 3–4 h after dosing, peak action detected 8–12 h after administration, and convincing evidence of 24-h duration of action [26, 27]. The branded formulation is administered as an isopropyl ester latanoprost prodrug and is absorbed through the cornea, where it is hydrolyzed by esterases to its biologically active acid form (latanoprost acid) [26, 28]. Once in systemic circulation, the active acid undergoes hepatic metabolism via fatty acid β-oxidation and rapid plasma elimination. The half-life is estimated to be 17 min, with subsequent excretion observed from the kidneys [28]. As branded latanoprost was the first prostaglandin analogue developed, it was initially compared with timolol maleate, the established at the time first-line treatment for glaucoma to gain FDA and EMA approval [29, 30]. In pivotal approval studies, at 6 months, latanoprost dosed in the evening demonstrated superior efficacy compared with timolol administered twice daily, achieving a mean IOP reduction of 6.7 mmHg versus 4.9 mmHg with timolol [29]. Moreover, branded latanoprost administered in the evening led to a significant 32% reduction in diurnal IOP after 1 year of treatment [31].

Most subsequent post-marketing, real-life, and 24-h IOP studies have shown latanoprost to be superior to timolol in overall IOP lowering [27, 30], but whether this difference is clinically meaningful remains uncertain. However, a meta-analysis conducted by Zhang and colleagues [32] involving 1256 patients across 11 trials comparing branded latanoprost to timolol found that latanoprost achieved an IOP reduction that was 5 mmHg greater than that of timolol. When compared with other PGAs, branded latanoprost also demonstrates good diurnal efficacy. A network meta-analysis of 20,275 participants across 114 randomized controlled trials found latanoprost to be the second most effective agent for IOP reduction, lowering baseline IOP at 3 months by 4.85 mmHg just behind bimatoprost (5.61 mmHg), being similar to travoprost (4.83 mmHg) and tafluprost (4.37 mmHg) [8]. Cumulative evidence suggests that, when PGAs are administered in the evening, they are more efficacious than when dosed in the morning [7]. With regard to comparative 24-h efficacy of PGAs, in a double-masked, crossover 24-h study, Konstas and colleagues [33] compared the 24-h efficacy of branded latanoprost with that of branded bimatoprost in patients with POAG, and reported that bimatoprost provided statistically superior 24-h efficacy, but the overall difference between groups was small (16.7 ± 2.4 vs. 17.3 ± 2.8 mmHg; p = 0.01). Differences may also exist in relative 24-h efficacy of PGAs when employed in the treatment of other glaucomas. For instance, in a direct crossover comparison between branded latanoprost and branded travoprost in subjects with exfoliative glaucoma, travoprost provided significantly lower IOP control, at the evening 18:00 time point [34].

Importantly, at present, regulatory guidelines do not require bioequivalence clinical studies directly comparing branded preserved latanoprost with its generic counterparts [23]. Nevertheless, several studies have evaluated their comparative efficacy and safety, with conflicting outcomes. A multicenter randomized trial involving 184 patients, performed in Italy, confirmed the non-inferiority of a generic latanoprost formulation by showing no significant difference in IOP-lowering efficacy compared to branded latanoprost [35]. Similarly, a prospective randomized study conducted in Greece on 60 treatment-naïve patients with open-angle glaucoma or ocular hypertension, compared the clinical efficacy and tolerability of branded latanoprost with two generic latanoprost formulations and found no statistically significant difference in IOP reduction, with mean reductions of 7.0 mmHg for branded latanoprost, and of 7.46 mmHg, and 7.3 mmHg, respectively, for the two latanoprost generics [17]. A 2019 meta-analysis further supported this assumption with the analysis of 6 randomized trials with moderate quality of evidence, indicating no statistically significant difference in terms of IOP reduction between branded and generic PGAs, including latanoprost [36].

However, other studies have reported differences in clinical performance between branded and generic latanoprost preparations. Indeed, a crossover Indian study with 30 subjects reported a greater mean IOP reduction at 12 weeks with branded latanoprost (− 9.35 mmHg) compared to a generic latanoprost formulation (− 5.76 mmHg) [37]. These authors observed that, when switching from generic to branded latanoprost, a 4.3% IOP decrease occurred, while switching in the opposite direction resulted in an 8.8% increase [37]. Another study conducted in Lithuania, involving 35 patients with open-angle glaucoma, found that, while mean IOP values were not significantly different between groups, branded latanoprost was more successful in achieving low IOP target levels below 14 mmHg, implying a potential benefit employing branded latanoprost in the long-term management of glaucoma [38]. A third crossover study in Israel investigated 19 patients and did not observe a statistically significant difference, but noted a trend favoring branded latanoprost [39]. Finally, a retrospective analysis by Kim and colleagues [40] reported a better clinical outcome when employing generic latanoprost compared to branded latanoprost and other branded PGAs, based on a reduced need for additional medications and surgical interventions, rather than just direct IOP comparisons. The authors, however, did not offer sufficient evidence to support this conclusion [40].

Comparing the Tolerability of Branded Versus Generic Latanoprost

The inactive ingredients of branded latanoprost consist of sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, water for injection, and 0.02% BAK employed as a preservative [26]. The presence of BAK provides antimicrobial protection and is thought to enhance drug permeability through the cornea [42, 43]. At the same time, however, BAK is known to induce a progressive, insidious, concentration-related cytotoxic effect on the ocular surface [41], which can lead to the development, or exacerbation of glaucoma treatment-related ocular surface disease (GTR-OSD) [42, 43]. As a result, BAK-containing ophthalmic solutions have been associated with progressive conjunctival fibrosis which not only reduces ocular tolerability but can also diminish the success of future glaucoma surgery [44]. It should be noted that the 0.02% concentration of BAK in branded latanoprost 0.005% solution was always notably high, as it represents the upper limit of the typical BAK concentration range used in ophthalmic formulations, which generally falls between 0.004 and 0.02% [42, 45]. Indeed, branded latanoprost’s BAK concentration is approximately two times higher than that seen in other glaucoma eyedrops, raising concerns about its negative impact on the ocular surface with long-term use [42, 46]. This point merits particular attention, as glaucoma is a lifelong disease that requires continuous therapy for decades [47]. Differences in concentration or type of inactive ingredients (particularly BAK) may affect not only the formulation’s efficacy and stability but also patient tolerability and adherence, which are critical factors in the long-term success of pharmacotherapy in glaucoma.

Unfortunately, to date, no long-term study has investigated the precise impact of BAK toxicity upon therapy tolerability, nor assessed the long-term rate of GTR-OSD with either branded or generic preserved latanoprost [46]. Of interest, a prospective, randomized 16-week study comparing branded versus two generic latanoprost formulations highlighted differences in overall tolerability as measured by the Ocular Surface Disease Index (OSDI) [17]. Despite the assumed similarity in the composition of branded and generic latanoprost, patients using branded latanoprost reported more favorable OSDI scores, indicating a better tolerability profile [17]. This outcome may be attributed to possible differences in BAK concentration between branded and generic latanoprost preparations despite claims of similar composition. More specifically, according to a study that compared active and inactive ingredients of branded and two latanoprost generics, only branded latanoprost contained 100% of the labeled BAK concentration (0.2 mg/ml), while the two generic formulations exhibited 105% (0.21 mg/ml) and 95% (0.19 mg/ml), respectively, of the labeled BAK amount [48]. The variability in BAK content has also been highlighted in a German study performed by Leitritz and colleagues [18], which measured the concentration of active ingredients in 23 latanoprost generics using high-performance liquid chromatography. These authors reported BAK concentration in generic latanoprost to vary from − 2.5 to + 11.5% compared with branded latanoprost [18]. In contrast, a Canadian study by Hallaji and colleagues [49] observed no significant difference in BAK concentration between branded and generic latanoprost. These findings suggest that, although in theory latanoprost formulations are supposed to be qualitatively and quantitatively equivalent, subtle and sometimes manifest differences appear to exist in terms of precise composition (including BAK concentration), and consequent physicochemical properties possibly leading to variations in clinical performance and tolerability.

Comparing the Physicochemical Properties of Branded Versus Generic Latanoprost

Several laboratory studies have focused on the analysis of the physicochemical properties and formulation consistency of branded versus generic latanoprost. According to Leitritz and colleagues [18], latanoprost generics in Germany contained less than 50 μg/ml of latanoprost, representing a 7.39% reduction compared with branded latanoprost, while the pH showed no statistically significant difference [18]. A study conducted in India compared the physicochemical characteristics between branded latanoprost and three latanoprost generics at room temperature [50]. Interestingly, the concentration of the active ingredient varied between the solutions evaluated. Indeed, two of the generics contained 13.28% and 18.20% more active ingredient than branded latanoprost, thus exceeding the allowed difference limit for approval [50]. This resulted in these generics having a higher amount of active drug per drop without commensurate difference in drop size, thus increasing the potential toxicity of the active ingredient [50]. Additionally, the authors observed a statistically significant difference in the pH of the samples evaluated with branded latanoprost exhibiting a pH of 7.05, while the two generics demonstrating pHs of 7.11 and 7.13, respectively. The authors suggested that this difference could impact ocular tolerability [50]. Branded latanoprost also demonstrated significantly lower mean osmolality (301.6 mOsm) compared to the two generics (322.20 mOsm and 382.20 mOsm, respectively) [50]. Finally, a statistically significant difference was noted in specific gravity between branded latanoprost and one of the generics (1.007 vs. 0.980) [50]. In theory, differences in osmolality and specific gravity may lead to increased ocular irritation and tissue damage, and may conceivably affect both the stability and the release of the active ingredient of the generic formulations.

Of interest, a study by Kolko and colleagues [51], conducted in Denmark, also highlighted differences, with a significantly higher pH in generic latanoprost solutions compared to branded latanoprost [51]. Branded latanoprost exhibited a significantly lower pH of 5.99 compared with the evaluated latanoprost generics, which ranged from 6.70 to 6.82 [51]. This study raises concerns not only for the pH differences between branded and generic latanoprost preparations in Denmark but also in view of the substantial difference in measured pH values between branded latanoprost in this study and that conducted in India. This difference may be attributed to variations in measurement equipment, and inter-factory or regional differences in latanoprost production and manufacturing. The Danish study further revealed variability in viscosity between the tested formulations, suggesting differences in inactive ingredients that could hypothetically impact drug delivery and efficacy [51]. Moreover, there was an appreciable variation in drop volume, ranging from 40 to 46 μL per latanoprost drop and total bottle volume [51]. Although generic formulations generally provided more drops per bottle, branded latanoprost required the least pressure to dispense a drop, indicating easier administration, which could enhance patient convenience [51]. On the other hand, a study conducted in the United States comparing drop count and actual bottle fill volume between branded and generic latanoprost confirmed a heterogeneity between the products [21]. This finding suggests that differences in bottle volume and the number of drops dispensed may not solely exist between branded and generic formulations but may also exist across different countries and manufacturers, further contributing to inconsistencies in latanoprost dosing and patient experience.

Performance of Branded vs. Generic Latanoprost with Temperature Fluctuations

Since introduction to the market, proper storage conditions were considered critical for preserving the stability and efficacy of latanoprost preparation due to a well-documented sensitivity to temperature fluctuations. According to the branded latanoprost packaging insert, unopened bottles of latanoprost ophthalmic solution must be stored under refrigeration at 2–8 °C, and, during shipment, they may tolerate temperatures up to 40 °C for a maximum of 8 days [26]. Once a latanoprost bottle is opened for use, it is specified that it may be stored at room temperature up to 25 °C for up to 6 weeks [26]. A real-world, clinic-setting study by Varma and colleagues [52] investigated the stability of latanoprost in used bottles from patients, where bottles had been stored at room temperature with daily highs ranging from 21 °C to 35 °C, for 4–6 weeks [52]. This study reported that 94% of bottles maintained latanoprost concentrations within 90–110% of the labeled amount [52]. However, in another real-world study, Paolera and colleagues [53] also examined the state of branded latanoprost after patient use, and reported that, after a mean use of 43.9 days, only 88.1% of the active ingredient of latanoprost remained, a finding that suggests significant degradation over time [53]. Furthermore, a laboratory study conducted by Morgan and colleagues [53] in the United States demonstrated that latanoprost undergoes significant degradation when exposed to elevated temperatures and ultraviolet light, with a 10% loss of active ingredient after just 8.25 days exposed at 50 °C, and this further accelerated to the same threshold in only 1.32 days when exposed at 70 °C [54]. Another laboratory trial conducted in India, showed that incubation of branded latanoprost at 40 °C reduces its concentration by 47% [55].

Kahook and colleagues [48] investigated the concentrations of active ingredients and BAK in branded versus two generic latanoprost formulations, using liquid chromatography–mass spectrometry under room temperature conditions and after 30 days of heat exposure up to 50 °C. Although the generics initially contained 10% more active ingredient than labeled (111.4% and 114.9%, respectively), they subsequently demonstrated significantly greater degradation than branded latanoprost after heat stress, raising concerns about their reliability in real-world conditions when temperatures exceed typical room temperature [48]. More specifically, the active ingredient in branded latanoprost degraded to 94.24% and 90.37% of its original concentration after 30 days of exposure to 25 °C and 50 °C, respectively. In contrast, the first generic latanoprost formulation degraded more sharply to 78.69% at 25 °C and 69.84% at 50 °C, while the second generic latanoprost formulation degraded to 78.69% and 65.18%, respectively, under the same conditions [48]. Moreover, latanoprost generic formulations exhibited higher concentrations of particulate matter larger than one micron, which could potentially worsen ocular surface disease [48]. These findings underline latanoprost's sensitivity to thermal and UV stress, and highlight the importance of proper storage to prevent degradation that could compromise therapeutic effectiveness especially in hot climates with high temperature. At the same time, since generic latanoprost formulations exhibit greater degradation when exposed to heat, in regions with warm or tropical climate, their use should be approached with caution.

Discussion

The majority of head-to-head clinical trials suggests that preserved branded and generic latanoprost preparations provide, by-and-large, comparable IOP reduction, supporting the wide clinical use of latanoprost generics worldwide (Table 2) [17, 35, 36]. At the same time, though, there is some dissenting evidence in some countries reporting better overall efficacy with branded latanoprost, especially when a lower target IOP is desirable [37–40]. These inconsistencies may reflect significant variations in formulation composition, level of excipients, preservative concentration, and varied performances of the active ingredient under diverse environmental conditions. The influence of such differences in long-term tolerability, and adherence with branded versus generic latanoprost, remains unclear. These findings reveal a complex picture that questions the assumption of full bioequivalence between branded and generic latanoprost. To what extent such factors influence long-term therapeutic outcomes can only be captured with long-term efficacy trials, which, at present, are not available. A cautious interpretation would suggest that most preserved latanoprost generics appear to be effective and cost-efficient alternatives, but branded preserved latanoprost may still be a better option in patients with more vulnerable ocular surfaces, in those who are on multiple therapies, and in those with advanced disease for whom particularly low IOP targets are desirable.

Table 2.

Summary of the clinical studies comparing branded versus generic latanoprost ophthalmic solution

Study	Place	Type	Duration	Sample size	Efficacy outcome	Tolerability
Diagourtas et al. 2018 [17]	Greece	Prospective randomized study	16 weeks	60 patients	No statistically significant difference	Branded better tolerability (OSDI)
Digiuni et al. 2013 [35]	Italy	Randomized multicenter control trial	12 weeks	184 patients	Generic non-inferior to branded	N/A
Narayanaswamy et al. 2007 [37]	India	Crossover study	24 weeks	30 patients	Branded significantly better	N/A
Egan et al. 2013 [38]	Lithuania	Crossover study	8 weeks	35 patients	Branded significantly better	N/A
Golan et al. 2015 [39]	Israel	Crossover study	4 weeks	19 patients	No statistically significant difference	N/A
Kim et al. 2018 [40]	USA	Retrospective study	N/A	10,467 patients	Generic reduced need for additional medications and surgical interventions	N/A

N/A not applicable, OSDI Ocular Surface Disease Index

Beyond efficacy, preservative content and physicochemical properties of eyedrops are important considerations in long-term glaucoma therapy. Topical antiglaucoma medications contain preservatives and excipients to optimize sterility and pharmacokinetics [41, 42]. The commonest preservative employed in ophthalmic formulations is BAK, a quaternary ammonium that acts as a detergent by disrupting lipids on tear film and cellular membranes, denaturing proteins, and loosening intracellular junctions [43, 46]. Due to its long retention on corneal and conjunctival tissues after administration of a single 30-μL BAK-containing eyedrop, BAK may be detectable up to 7 days following instillation [46]. Preserved branded and generic latanoprost preparations contain BAK at a relatively high concentration, which may accumulate over time and contribute to the progressive development and deterioration of GTR-OSD [42, 43, 46, 56], as well as potentially undermining the outcome of future surgical interventions [43, 44].

An abundance of scientific evidence suggests that BAK and other preservatives elicit extensive toxic effects upon the ocular surface and underlying tissues [46, 55–60]. Epidemiological data have demonstrated the prevalence of GTR-OSD to vary between 45% and 60% in patients with glaucoma, with up to 78% of subjects manifesting some evidence of tear film disruption [43, 46, 56, 61]. The diversity of these numbers directly correlates with the number of antiglaucoma medications used, the daily preservative burden to the tissues, whether some degree of ocular surface disease (OSD) pre-existed glaucoma therapy, and ageing and hormonal imbalances [46, 62]. At present, it remains unclear how long it takes for preserved latanoprost (branded or generic) to elicit clinically detectable and symptomatic GTR-OSD when employed as monotherapy. Available studies with preserved latanoprost have been limited in duration of follow-up. Evidently, for GTR-OSD to develop and become clinically manifest when a patient is treated with only one drop of latanoprost a day, it can take up to a year or longer. This explains why many short-term studies have likely not revealed the true rate of tissue damage, nor the ensuing impact in long-term tolerability. This is an important drawback in determining overall tolerability between branded and generic latanoprost. Longer-term salient studies are desirable in the future.

As with other medications, another limiting factor in delineating the precise rate and severity of progressive GTR-OSD with latanoprost therapy (branded or generic) remains the lack of sensitive and reliable detection of the condition and its severity in clinical practice [46, 56, 61]. Similarly to dry eye disease, the diagnosis of GTR-OSD is often problematic due to an inconsistent correlation between reported symptoms and observed signs [56, 62]. A consensus needs to be reached concerning the accurate and reliable sets of parameters for determining an objective GTR-OSD diagnosis and guiding subsequent follow-up. This discrepancy arises mainly due to the limited consistency of commonly used diagnostic and monitoring tests, the natural variability of the disease process, the subjective nature of symptoms, and individual variations in pain thresholds and cognitive responses to questions about ocular sensation [56, 62]. If we can establish a reliable set of diagnostic tools in the future for optimal focused disease-specific GTR-OSD diagnosis and monitoring, this would greatly facilitate comparisons between the various formulations. Additionally, the use of preservative-free latanoprost in future studies may serve as a suitable benchmark for assessing long-term tolerability [47].

Beyond preservative toxicity concerns, laboratory studies reveal considerable variability in the physicochemical properties of generic latanoprost formulations [18, 50, 51]. Differences in active ingredient concentration, pH, osmolality, specific gravity, viscosity, and drop volume can influence drug stability, ocular tolerance, and delivery efficiency [18, 21, 50, 51]. Moreover, some generics exceed approved active ingredient concentrations, potentially increasing toxicity, while variations in pH, osmolality, or drop characteristics may reduce comfort and adherence [50]. These findings suggest that therapeutic equivalence should not be based solely on the basis of IOP reduction. Indeed, even subtle differences in preservative content and formulation characteristics may progressively worsen both tolerability and long-term outcomes, particularly in patients with glaucoma on multiple medical therapy for decades. Thus, long-term controlled trials are desirable to fully assess the clinical impact of differences between branded and generic latanoprost preparations. In the meantime, careful monitoring of the ocular surface and patient tolerability and adherence is recommended when patients are under treatment with preserved generic latanoprost formulations.

Storage and stability are additional factors to consider when comparing branded with generic latanoprost. Latanoprost is sensitive to temperature and light, with degradation accelerating under elevated temperatures and ultraviolet exposure [48, 52, 54, 55]. While in theory only unopened latanoprost bottles require refrigeration, real-world studies have shown that, in some countries, even room-temperature storage can lead to tangible loss of active ingredients over time [48, 52, 54, 55]. Importantly, available evidence suggests that generic formulations degrade more rapidly than branded latanoprost under heat stress, and may end up with higher levels of particulate matter, which may worsen GTR-OSD [48]. Understandable, these findings are particularly relevant in hot, or tropical, climates, where improper storage will meaningfully reduce therapeutic efficacy.

A major limitation in the reviewed literature is the wide range of latanoprost generics on the market. Consequently, each study can assess only a small sample, making it difficult to generalize findings. Moreover, the heterogeneity observed in available studies, the short follow-up periods in assessing tolerability, and the small sample size in the majority of the studies, further limit the generalizability of the findings. Given current regulatory standards and the variability observed, it remains uncertain whether all generics can truly match the performance of branded latanoprost formulation. Therefore, additional physicochemical analyses should be sought to assess the consistency, stability, and formulation quality of all commercially available generic formulations. Only controlled long-term trials, with direct comparisons and real-world outcome studies evaluating the therapeutic equivalence of each latanoprost generic, can reassure and facilitate their selection in clinical practice. Moreover, future studies should focus, beyond efficacy, on the tolerability of generic preserved latanoprost preparations versus their branded counterpart and preservative-free latanoprost formulations.

Conclusion

Branded preserved latanoprost represents a therapeutic standard in glaucoma care, developed through extensive research, comparative efficacy studies, and strict quality control. Preserved generic latanoprost preparations offer a significant cost benefit when employed as an alternative option. Available evidence demonstrates several subtle and sometimes manifest differences between branded and generic latanoprost preparations. Documented differences include active ingredient concentration, BAK content, pH level, osmolality, particulate content, and drop size. Of interest, degradation under adverse temperature conditions is greater with generic as opposed to branded latanoprost. Nevertheless, as yet, it is not clear to what extent laboratory differences translate into clinical outcomes. It is conceivable that recorded differences ultimately influence long-term efficacy, tolerability, ocular surface health, and adherence. To what extent these differences play a role in glaucoma care over the long term remains to be determined. Only long-term, high-quality controlled trials can determine the significance and clinical impact of reported differences in latanoprost generics. Until this information becomes available, latanoprost therapy should be individualized, while careful patient monitoring is recommended, and stricter regulatory oversight should be sought, including a potential reduction in the variability of active and inactive substances to ensure the safety and consistency of all available generic latanoprost formulations.

Author Contribution

Chara Tsiampali and Iordanis Vagiakis have contributed equally to this manuscript. All four authors (Chara Tsiampali, Iordanis Vagiakis, Chrysanthi Sardeli, and Anastasios G. Konstas) have contributed significantly in the preparation of this review, meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Funding

This review has not been funded by any public or private body. No funding or sponsorship was received for the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the preparation of the current review.

Declarations

Conflict of Interest

Chara Tsiampali and Chrysanthi Sardeli: no disclosures; Iordanis Vagiakis: travel support from Vianex; Anastasios G. Konstas: research funding from Bayer, Omni Vision, Santen and Théa; fees for consultancy and lectures with travel support from Esteve, Intermed, Santen, Théa and Vianex. Prof. Anastasios G. Konstas is an Editorial Board member of Advances in Therapy. He was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.