Loteprednol etabonate for inflammatory conditions of the anterior segment of the eye: twenty years of clinical experience with a retrometabolically designed corticosteroid

ABSTRACT

Introduction: Topical corticosteroids are an important pharmacotherapy for the management of various inflammatory conditions affecting the anterior segment of the eye. However, medications in this class are associated with well-known risks including increased intraocular pressure (IOP) and development of cataracts. The topical corticosteroid loteprednol etabonate (LE) was developed with the specific intention of minimizing these side effects.

Areas covered: The focus of this review is to examine published efficacy and safety data for LE, a drug engineered to undergo rapid metabolism to inactive metabolites with the goal of improved safety. Two decades of clinical research focused on LE formulations are reviewed, including the use of LE in combination with tobramycin. The cumulative body of experience affirms the concept that the molecular design of LE confers certain safety benefits without compromising the desired anti-inflammatory efficacy of a topical corticosteroid.

Expert opinion: Loteprednol etabonate is a mainstay for topical therapy of a wide variety of commonplace and niche conditions of the ocular surface and the anterior segment, including in the healing post-operative patient. Its versatility and safety allow eye care providers to recommend both acute induction as well as chronic maintenance therapy with appropriate follow-up.

KEYWORDS:

• Anterior segment
• cataract
• dry eye
• conjunctivitis
• intraocular pressure
• loteprednol etabonate
• ocular surface disease
• post-operative ocular inflammation
• retrometabolic drug design
• uveitis

1. Introduction

Ophthalmic corticosteroids elicit numerous potent anti-inflammatory effects and are a standard of care for the management of anterior segment inflammation. Loteprednol etabonate (LE) is an ocular corticosteroid that was engineered with the goal of maintaining robust and effective corticosteroid anti-inflammatory activity while minimizing typical risks associated with this class of medication, notably elevated intraocular pressure (IOP) and cataract formation [1]. Although the chemical structure of LE shares many similarities with other corticosteroids, its molecular configuration was purposefully designed with the goal of improved safety without sacrificing anti-inflammatory effectiveness.

LE ophthalmic suspension 0.5% and 0.2% formulations were first approved by the US Food and Drug Administration in 1998. Since then, additional formulations have been developed, including an ointment, a tobramycin combination suspension, and a gel approved in 2012, all at a concentration of 0.5%. Over the past two decades, these formulations have been studied in a variety of anterior segment inflammatory conditions.

The purpose of this review was to describe the rationale for the development of LE, the first retrometabolically designed topical corticosteroid to be commercially marketed, and provide an overview of published preclinical and clinical data, including safety data with regard to IOP elevation and cataract formation. Studies were identified through medical literature searches performed in PubMed through September 2017 using the term ‘loteprednol etabonate’ and limited to English-language reports. Bibliographies of identified publications were also scanned. All identified clinical studies which used a commercially marketed formulation of LE were included.

2. Retrometabolic drug design

For the treatment of anterior segment inflammatory conditions, administration of corticosteroids via the topical route is generally favored, given that distribution of systemically delivered medications into ocular tissues is limited by the blood–retinal barrier. Through topical application, drug delivery to the anterior segment is maximized while systemic effects, such as suppression of the hypothalamic-pituitary-adrenal-axis, are minimized. However, topical ophthalmic corticosteroid use can result in ocular complications including IOP elevations, posterior subcapsular cataract formation with long-term use, secondary infection, and delays in corneal wound healing [2–5]. The possibility of lessening the risks of adverse events (AEs) with topical corticosteroid use became apparent as research revealed that some of the unwanted effects of corticosteroids are mediated through lingering genomic-level activity of the corticosteroid-glucocorticoid receptor (GR) complex beyond that responsible for eliciting the desired anti-inflammatory effects [6].

The concept of retrometabolic drug design, introduced by Bodor and colleagues in the 1970s [7], entails a process of designing a compound that will achieve a desired pharmacologic action followed by rapid metabolism into inactive metabolites to avoid unwanted effects. The process begins with identifying a metabolite of the reference compound that has no apparent pharmacologic activity and structurally modifying that molecule into an isosteric/isoelectronic analog (Figure 1) [8]. Thus, drugs can be purposefully designed to have a lower risk for AEs, while retaining a potency that is comparable to the reference compound. It is critical that the new compound have sufficient metabolic stability to reach its intended receptor and produce the intended pharmacological outcome. Also, and of equal importance, there must be a balance between pharmacokinetic and pharmacodynamic attributes of the drug such as solubility, lipophilicity, distribution into tissues, receptor binding, and metabolic deactivation rate. Bodor originally used the term ‘soft drug design’ to underscore the improved safety profile of compounds designed through this process, but that term was later replaced, in large part, by the more descriptive term ‘retrometabolic drug design.’

Figure 1. Concept of retrometabolic drug design in which a new lead molecule is reverse-engineered based on an inactive metabolite of a previous leading compound (adapted with permission from reference [9]).

As the basis for corticosteroid retrometabolic engineering, Bodor used Δ1-cortienic acid, an inactive metabolite of pred-nisolone acetate (PA). Bodor and colleagues created a series of analogs by chemical substitutions that preserved desirable corticosteroid anti-inflammatory activity while ensuring efficient metabolism to inactive metabolites, thus reducing the potential for AEs. The developmental steps have been reviewed in greater detail elsewhere [6]. Bodor and colleagues synthesized more than 100 molecules derived from the Δ1-cortienic acid structure, the most promising of which was LE [10]. Prednisolone, like many other corticosteroids, has a ketone group at the carbon-20 (C-20) position; the LE molecule has a 17β-chloromethyl ester at the C-20 position in place of the ketone group (Figure 2) [11], as well as a 17α-etabonate moiety. The expected consequence of the modification was that LE would be rapidly de-esterified to its inactive carboxylic acid metabolite after eliciting the desired pharmacologic activity. A number of other desirable characteristics contributed to the identification of LE as the most promising molecule for further development, including a high degree of lipophilicity in order to enhance penetration across biological membranes [12], evidence of potent GR binding affinity approximately 4.3-fold greater than that of dexamethasone [13], and a therapeutic index markedly greater (more than 20-fold) than other corticosteroids (hydrocortisone 17α-butyrate, betamethasone 17α-valerate, clobetasone 17α-propionate) [7]. The placement of an ester group at the C-20 position had the added benefit of lessening the risk of cataract formation compared to C-20 ketone-based steroids [14,15]. C-20 ketone steroids can form Schiff base intermediates with lysine residues of lens protein and eventual stable amine-substituted adducts following Heyns rearrangement; C-20 ester steroids, in contrast, do not form such adducts [14].

Figure 2. Prednisolone-based structure and metabolic fate of loteprednol etabonate. The ketone group at the prednisolone carbon-20 (C-20) position is replaced by a 17B-chloromethyl ester (indicated in gray) in the LE molecule. LE undergoes rapid de-esterification to the inactive ∆1-cortienic acid after exerting its effect. (Reproduced from reference [11] with permission of John Wiley and Sons).

3. Preclinical and pharmacokinetic studies

Numerous preclinical investigations demonstrated that the pharmacologic characteristics of LE are, in fact, consistent with those anticipated by Bodor when he designed the molecule. In rabbit models, the highest concentrations of LE were detected in the cornea and conjunctiva, followed by the iris/ciliary body, and much lower levels in the aqueous humor (100-fold lower than corneal concentrations) [13,16]. Studies in human subjects noted measurable levels of LE in tear fluid through 24 h after instillation [17] and plasma levels of LE and its major (inactive) metabolite, Δ1-cortienic acid, below the level of quantification (1 ng/mL) [18], indicating a low risk of systemic exposure. The observed low aqueous humor levels of LE highlighted the possibility that this novel corticosteroid might pose little risk for IOP elevation, and rabbit studies confirmed this assumption [19]. In animal models of ocular disease and human cell tissue studies, LE demonstrated similar or greater anti-inflammatory activity as other glucocorticoids as measured by greater GR migration to the nucleus (a marker for comparing drug efficacy) relative to PA or fluorometholone [20] and reductions in cytokine and prostaglandin E2 release comparable to dexamethasone [21]. Preclinical and pharmacologic data with LE have been reviewed in greater detail elsewhere [6].

4. Clinical studies

All 5 formulations of LE (suspension [0.2% and 0.5%], 0.5% ointment, 0.5% gel, 0.5% suspension combined with tobramycin 0.3%) have undergone randomized, controlled, clinical safety and efficacy trials. Available published clinical study experience with LE is reviewed in the following paragraphs by formulation. Randomized, controlled, clinical trials for the major therapeutic usage categories of ocular inflammatory diseases and management of postoperative inflammation and pain are also outlined in Tables 1 and 2, respectively.

Table 1. Randomized, controlled, clinical studies of loteprednol etabonate for ocular inflammatory diseases.

			Safety Findings
Study	Study Treatment(s) and Duration^a	Efficacy Findings	IOP	Other
Giant Papillary Conjunctivitis
[23]	4 weeks LE 0.5% suspension QID (n = 57) vs. placebo QID (n = 56)	(i) LE reduced papillary severity score (P ≤ 0.02 vs. placebo, days 7, 14, 21, and 28) (ii) Change in papillae AUC vs. placebo −13.4 vs. −7.5 (P < 0.001) (iii) Investigators global assessment better with LE (P = 0.017 vs. placebo)	IOP remained stable in LE-treated group, but decreased in placebo group (difference between groups, P < 0.05 at Day 21)	No treatment-related adverse ocular changes No infection of external ocular tissues or evidence of steroid-induced keratopathy or uveitis
[24]	6 weeks LE 0.5% suspension QID (n = 111) vs. placebo QID (n = 109)	(i) Reduced papillary severity at final visit: LE 75%; placebo 50% (P < 0.001) (ii) Reduced itching at final visit LE 92%; placebo 76% (P = 0.001) (iii) Improved lens tolerance at final visit: LE 84%; placebo 66% (P = 0.002 vs. placebo)	↑ IOP (≥10 mm Hg at ≥1 visit): 3% for LE group; 0% for placebo (P = 0.099) One patient discontinued LE early at week 5 due to elevated IOP (28 mm Hg OD and 30 mm Hg OS)	Discontinuations due to AEs (other than ↑ IOP): (i) 3 in LE group (flu-like symptoms, severe headache, taste perversion) (ii) 3 in placebo group (nausea and dizziness, corneal ulcer, twitching eyes) Other signs/symptoms were similar in both treatment groups No serious AEs
[25]	6 weeks LE 0.5% suspension QID (n = 110) vs. vehicle QID (n = 113)	(i) Reduced papillary severity at final visit: LE 78%; vehicle 51% (P = 0.001) (ii) Reduced itching at final visit: LE 95%; vehicle 81% (P < 0.001) (iii) Improved lens tolerance at final visit: LE 87%; vehicle 77% (P = 0.053)	↑ IOP (≥10 mm Hg): 7% vs. 0% n = 8 for LE n = 0 for vehicle 3 LE-treated patients discontinued treatment early due to elevated IOP (max of 24–38 mm Hg)	1 LE and 1 vehicle patient discontinued treatment due to conjunctivitis Other signs/symptoms were similar in both treatment groups No serious AEs reported
Seasonal Allergic Conjunctivitis
[27]	Prophylaxis 6 weeks LE 0.5% suspension QID (n = 146) vs. vehicle QID (n = 147)	(i) Reduced composite of itching and BCI (P = 0.001 vs. vehicle) (ii) Investigators global assessment (P < 0.001 vs. vehicle)	↑ IOP (≥10 mm Hg): n = 0 (0%) for LE n = 2 (1.4%) for vehicle 1 LE-treated patient discontinued treatment early due to elevated IOP (24 mm Hg)	Discontinuations due to AEs (other than ↑ IOP): (i) 3 in LE group (ocular irritation, headache, rhinitis, flu symptoms, atrial fibrillation) (ii) 6 in vehicle group (2 patients with ocular allergic reactions, 2 patients with nonocular pain, viral keratitis, rhinitis) Other symptoms were similar in both treatment groups; no untoward ocular signs other than those of allergic conjunctivitis
[26]	Treatment 6 weeks LE 0.2% suspension QID (n = 66) vs. vehicle QID (n = 67)	(i) Reduced BCI (P = 0.006 vs. vehicle) and itching (P = 0.034 vs. vehicle) at 2 weeks (ii) Investigator global assessment at week 2 better: LE 79%; vehicle 47% (P < 0.001)	No ↑ IOP (≥10 mm Hg) 1 LE-treated patient discontinued early (week 1) due to IOP 9 mm Hg above pre-study baseline	≥1 AE: 68% vs. 90% (P = 0.002) Discontinuations due to AEs (other than ↑ IOP): (i) 1 in LE group (headache) (ii) 2 in vehicle group (severe itching, viral conjunctivitis) No serious AEs reported
[28]	Treatment 6 weeks LE 0.2% suspension QID (n = 67) vs. vehicle QID (n = 68)	(i) Reduced BCI, itching at 2 weeks: LE 80%; vehicle 44% (P ≤ 0.008) (ii) Investigator global assessment at week 2 better (P < 0.001 vs. vehicle)	↑ IOP (≥10 mm Hg): n = 1 (1.5%) for LE n = 1 (1.5%) for vehicle 1 vehicle patient discontinued early due to elevated IOP (30 [right eye]/35 [left eye] mm Hg)	Patients with no AEs: 36% (LE) vs. 19% (vehicle) (P = 0.035) Discontinuations due to AEs (other than ↑ IOP): (i) 1 in LE group (hospitalized after unrelated motor vehicle accident) (ii) 1 in vehicle group (spasm on instillation of drop) No serious AEs reported
[29]	Conjunctival Allergen Challenge Model Day of allergen challenge, 1 drop LE 0.2% (n = 20) or olopatadine 0.1% (n = 20) or vehicle (n = 10). (LE group given 2-week ‘load’ QID prior to challenge)	Assessments at 10, 15, and 20 min following allergen challenge: (i) Itching relief and redness prevention greater with olopatadine vs. LE at all time points (P ≤ 0.034). No significant difference between LE and vehicle.	Mean IOP in the LE 0.2% group increased significantly from 14.65 at baseline to 16.25 after 14 days (P < 0.001) (Olopatadine only given as 1 drop)	No AEs reported in any group
[30]	Treatment 2 weeks LE 0.2% suspension QID (n = 151) vs. olopatadine 0.1% solution BID (n = 149)	(i) Reduced BCI, itching at week 2 in both groups (P ≤ 0.0006 in favor of LE)	No ↑ IOP (≥10 mm Hg)	≥1 AE: 3.3% LE vs. 1.3% olopatadine ≥1 ocular AE: 2.0% LE vs. 1.3% olopatadine (P = NS) Ocular AEs (i) 1 LE patient each with: swollen eyelid (led to discontinuation), instillation-site abnormal sensation, instillation-site stinging (ii) 1 olopatadine patient each with epidemic hemorrhagic conjunctivitis (led to discontinuation), vision blurred Nonocular AEs: (i) 2 LE patients: 1 with both sinusitis and nasal septum deviation (considered serious, led to discontinuation), 1 with fibula fracture (ii) None in olopatadine group
[31]	Treatment 2 weeks LE 0.5% suspension QID (n = 20) or olopatadine HCl 0.1% BID (n = 20) or emedastine difumarate 0.05% BID (n = 20), or AT TID (n = 20)	(i) All active treatment groups significantly (P < 0.05) more effective than AT against ocular signs and symptoms at 2 weeks. No differences between active treatments	IOP not evaluated	AE data not reported (no indication evaluated). No clinically significant changes in visual acuity; no changes in fundus oculi in any group
Vernal Keratoconjunctivitis
[32]	LE 0.5% suspension or prednisolone acetate 1% or fluorometholone acetate 0.1% (each group, n = 20 patients/40 eyes) 2 weeks, QID	(i) All active treatment groups produced significant (P < 0.001) improvement in signs and symptoms from baseline to Week 4. LE similar to prednisolone, but significantly better than fluorometholone (P < 0.01) for all signs/symptoms except chemosis (all treatments similar) (ii) LE and prednisolone groups had similar mean visual acuity improvements, both higher compared with fluorometholone (P = 0.02)	Significantly (P < 0.001) elevation in mean IOP in prednisolone group only after day 3. 3 patients in prednisolone group dc/d study because of IOP elevation in Week 2	No other AEs reported in any group
Anterior Uveitis
[33]	6 weeks LE 0.5% suspension (n = 36) vs. prednisolone 1% (n = 34). Regimen: Days 0–7: 8 times/day Days 8–14: 6 times/day Days 15–21: QID Days 21+: tapered according to severity of uveitis	Patients with resolution (score of 0) by the final on-treatment visit (LOCF), LE vs. prednisolone: (i) ACC: 74 vs. 88% (P = NS) (ii) Flare: 71 vs. 81% (P = NS) (iii) Pain: 79 vs. 81% (P = NS)	↑ IOP (≥10 mm Hg): n = 0 (0%) for LE n = 1 (2.9%) for prednisolone	No patients discontinued from study because of AEs No serious AEs reported
[33]	4 weeks LE 0.5% suspension (n = 84) vs. prednisolone 1% (n = 91) Regimen: Days 0–7: Hourly, up to 16 times/day Days 8–14: Every 2 h, up to 8 times/day Days 15–21: QID Days 22–25: BID Dats 26–28: QD	Patients with resolution (score of 0) by the final on-treatment visit (LOCF), LE vs. prednisolone: (i) ACC: 72 vs. 87% (P = 0.015) (ii) Flare: 66 vs. 82% (P = 0.017) (iii) Pain: 90 vs. 85% (P = NS)	↑ IOP (≥10 mm Hg): n = 1 (1.2%) for LE n = 6 (6.6%) for prednisolone	Discontinuations due to AEs (other than ↑ IOP): (i) 2 in LE group (cystoid macular edema/decreased visual acuity, various ocular symptoms) (ii) 2 in prednisolone group (interstitial keratitis, increase in age-related macular degeneration) Otherwise, no serious AEs reported
Blepharokeratoconjunctivitis (BKC) or Blepharitis
[47]	(BKC) 2 weeks LE 0.5%/tobramycin 0.3% QID (n = 138) vs. dexamethasone 0.1%/tobramycin 0.3% QID (n = 138)	(i) Mean change [SD] in reduced composite signs and symptoms at day 15 (−15.2 [7.3] vs. −15.6 [7.7], P = NS) (ii) Investigator global assessment: 43.6 vs. 40.9% cured (P = NS)	↑ IOP (≥10 mm Hg): n = 0 for LE/T n = 1 (0.7%) for DM/T Mean IOP increase at day 7 (−0.1 mm Hg vs. 0.6 mm Hg, P = 0.04), day 15 (−0.1 mm Hg vs. 1.0 mm Hg, P = 0.01), and overall (1.6 mm Hg vs. 2.3 mm Hg, P = 0.02)	≥1 ocular AE: 2.9 vs. 6.5% (P = NS) (i) LE/T group: 1 subject each (allergic conjunctivitis, eye irritation, eye pain, increased IOP) (ii) DM/T group: 1 subject each (decreased lacrimation, foreign body sensation; 2 subjects (punctate keratitis); 5 subjects (increased IOP) No serious ocular AEs reported 4 subjects (2.9%) in each group reported a non-ocular AE (no infections) 2 subjects in the LE/T group discontinued due to AEs (1 each headache, allergic conjunctivitis) No clinically relevant findings/differences between treatment groups related to visual acuity or biomicroscopy
[48]	(BKC) 2 weeks LE 0.5%/tobramycin 0.03% QID (n = 180) vs. dexamethasone 0.1%/tobramycin 0.3% QID (n = 177)	(i) Improvement from baseline in composite signs and symptoms severity at day 15 in both groups (P < 0.0001 vs. baseline) (ii) Mean change [SD] in reduced composite signs and symptoms at day 15 (−11.6 [4.6] vs. −12.4 [4.7], P = NS)	↑ IOP (≥10 mm Hg): n = 6 (3.4%) for LE/T n = 13 (7.3%) for DM/T (P = NS) One eye in DM/T group experienced IOP ≥30 mm Hg Mean IOP increase at day 15: 1.33 mm Hg vs. 2.43 mm Hg (P = 0.004)	≥1 ocular AE: 13.0 vs. 23.2% (1 case bacterial keratitis in LE group) Nonocular AEs: (i) LE/T group: 1 subject each (mild nausea, moderate spinal disorder, mild headache, mild alopecia) (ii) DM/T group: 1 subject each (mild nausea, mild nasopharyngitis, mild dizziness) No serious AEs reported
[51]	(Blepharitis, pediatrics) LE 0.5%/tobramycin 0.3% (n = 72) or vehicle (n = 36) QID for 7 days followed by BID for 7 days along with warm compresses BID throughout the study	(i) Efficacy findings from this study were unclear due to improvements in all treatment groups	Mean IOP and IOP changes from baseline were not different between LE/T and vehicle treatment groups at any study visits No ↑ IOP (≥10 mm Hg)	No serious ocular AEs were reported; ≥1 treatment-emergent ocular AE: LE group – 3 (4.2%); vehicle – 2 (5.6%) ≥1 treatment-emergent nonocular AE: LE group – 6 (8.3%); vehicle – 2 (5.6%)
[50]	(BKC) LE 0.5%/tobramycin 0.3% BID (n = 20), dexamethasone 0.1%/tobramycin 0.3% BID (n = 20) for 3–5 days	Scores at 3–5 days of treatment, DM/T vs. LE/T: Ocular surface (1.8 vs. 3.4), blepharitis (0.9 vs. 1.35), discharge (0.2 vs. 0.6), and conjunctivitis (0.15 vs. 0.6) (all P ≤ 0.025) Corneal punctate epithelial keratopathy scores were not significantly different between treatments	No differences between groups for IOP findings	No AEs reported No clinically meaningful changes in visual acuity
[51]	(BKC, pediatrics) 2 weeks LE 0.5%/tobramycin 0.3% QID (n = 34), LE 0.5% QID (n = 35), Tobramycin 0.3% QID (n = 34), or vehicle QID (n = 34)	(i) Efficacy findings from this study were unclear due to improvements in all treatment groups	IOP not evaluated	No serious ocular AEs were reported; ≥1 ocular AE: LE/T group – 1 (2.9%); LE – 4 (11.4%); T – 0; vehicle – 0; ≥1 non-ocular AE: LE/T – 2 (5.9%); LE – 6 (17.1%), T – 6 (17.6%); vehicle – 5 (15.2%)
Dry Eye Disorders
[34]	(Keratoconjunctivitis sicca) 4 weeks LE 0.5% suspension QID (n = 32) vs. vehicle QID (n = 34)	(i) Reduced hyperemia at week 2 and week 4 (P = 0.0473 vs. vehicle) (ii) Subset analysis showed reduced central corneal staining, nasal bulbar conjunctival hyperemia, and lid margin injection at some visits (P < 0.05 vs. vehicle)	No ↑ IOP (≥10 mm Hg) No significant change in mean IOP	≥1 treatment-related AE: 16.7 vs. 23.5% (treatment-related ocular AEs included increased burning, redness, blurring of vision, foreign body sensation) No clinically significant changes in visual acuity or treatment-related abnormalities on slit-lamp examination, lens examination, or fundoscopy No treatment-related serious AEs
[35]	(Meibomian gland dysfunction) 2 months LE 0.5% suspension QID following eyelid scrubs with warm compresses BID (Group I; n = 34) vs. eyelid scrubs with warm compresses only BID (Group II; n = 36)	(i) Significantly lower levels of IL-6 (P = 0.007), IL-8 (P = 0.001), and IL-1β (P = 0.030) in Group I vs. Group II (ii) Significantly longer TBUT (P = 0.014) and lower (better) staining scores (cornea, conjunctiva, DEWS, Oxford) (P < 0.05) in Group I vs. Group II (iii) Significantly larger improvements in lid margin abnormality (P = 0.018) and meibum quality (P < 0.001) in Group I vs. Group II at 2 months compared to baseline (iv) Significant improvements in expressibility (P = 0.019), ocular irritation symptom score (P < 0.001), and MGD stage (P < 0.001), Group I vs. Group II at 2 months	No significant difference in mean IOP between groups at each time point. No ↑ IOP (≥10 mm Hg)	Authors noted there were no serious AEs; no other AE information provided
[36]	(Dry eye syndrome [DES]/GVHD) LE 0.5% suspension BID (n = 38 patients; n = 76 eyes) vs. tCSA 0.05% BID (n = 37 patients; n = 74 eyes) Treatment starting 1 month prior to, and for 12 months after, hematopoietic stem cell transplant	(i) Similar rates of DES incidence (P = 0.22) and progression (P = 0.41) between groups (ii) Significant increase in tear osmolarity for LE compared to tCSA at 12 months (P = 0.08) (iii) 38% rate of disease progression with tCSA compared to 26% rate with LE at 12 months	No difference between groups in IOP change from baseline to 12 months (P = 0.70) No ↑ IOP (≥10 mm Hg from baseline)	Mean visual acuity remained stable in both treatment groups
[37]	(Chronic dry eye disease) LE 0.5% suspension or AT QID for 2 weeks, followed by tCSA BID with either LE or AT BID for another 6 weeks LE group, n = 57 AT group, n = 55	(i) LE pretreatment significantly reduced tCSA stinging (P < 0.05) (ii) LE group demonstrated significantly greater OSDI improvement than AT. (iii) Onset of effectiveness was achieved after 15 days of LE + tCSA compared with 45 days for AT + tCSA	Mean IOP did not change in either treatment group	Ocular AE profiles were similar between treatment groups The most common ocular AEs were eye pain (LE, 7.0%; AT, 2.6%), reduced visual acuity (LE, 5.3%; AT, 3.2%), conjunctival hyperemia (LE, 5.3%; AT, 2.6%), and IOP increased (LE, 5.3%; AT, 1.3%) No cataract, hypotony, posterior capsular opacification, or surgical wound complications reported
[65]	(Mild-to-moderate dry eye) Treatment groups: 1) LE gel BID for 12 weeks (n = 36) 2) LE gel BID weeks 1–4, along with tCSA BID week 3–12 (n = 33) 3) tCSA BID for 12 weeks (n = 33)	(i) At 12 weeks, all treatments improved signs and symptoms of dry eye compared with baseline (P < 0.05)	IOP >21 mm Hg, n = 2: 1 each in LE and LE + tCSA groups at week 12	Few AEs (all ocular) with any of the 3 treatments, including burning, stinging, discomfort on instillation Biomicroscopy/ophthalmoscopy findings unremarkable No serious AEs

ACC: anterior chamber cells; AE: adverse event; AT: artificial tears; BCI: bulbar conjunctival injection; BID: twice daily; BKC: blepharokeratoconjunctivitis; DES: dry eye syndrome; IOP: intraocular pressure; GVHD: graft versus host disease; LE: loteprednol etabonate; LOCF: last observation carried forward; NS: not significant; QD: once daily; QID: four times daily; tCSA: topical cyclosporine A.

^aN values represent number of randomized patients unless indicated otherwise.

Adapted from [6] with permission of Hindawi.

Table 2. Randomized, controlled, clinical studies of loteprednol etabonate for postoperative inflammation.

			Safety Findings
Reference	Procedure, treatment duration, study treatments^a	Efficacy	IOP	Other
[41,43]	Postoperative cataract surgery with intraocular lens implantation; 2 weeks LE 0.5% suspension QID (n = 109 [ITT population]) vs. vehicle QID (n = 113 [ITT population])	(i) Resolution of ACI at final visit: 64 vs. 29% (P < 0.001 vs. vehicle) (ii) Treatment failure rate: 6% vs. 30% (P < 0.001 vs. vehicle) (iii) Investigator global assessment of treatment effect (P < 0.001 vs. vehicle) (iv) Grade 0 (no pain) at final visit: 85 vs. 54% (P = 0.003)	↑ IOP (≥10 mm Hg) n = 3 (2.8%) for LE n = 0 for vehicle Mean IOP decreased in both groups	≥1 AE: 58 vs. 80% (P < 0.001) Discontinuations due to AEs: (i) 2 in LE group (ocular inflammation, chest pain in patient with history of cardiovascular disease) (ii) 3 in vehicle group (ocular inflammation) Other serious AEs included: (i) 2 in LE group (endophthalmitis, myocardial infarction) (ii) 1 in vehicle group (cystoid macular edema)
[42,43]	Postoperative cataract surgery with intraocular lens implantation; 2 weeks; LE 0.5% suspension QID (n = 102) vs. vehicle QID (n = 101)	(i) Resolution of ACI at final visit: 55 vs. 28% (P < 0.001) (ii) Treatment failure rate: 7 vs. 32% (P < 0.001 vs. vehicle) (iii) Investigator global assessment of treatment effect (P < 0.001 vs. vehicle) (iv) Grade 0 (no pain) at final visit: 83 vs. 59% (P = 0.018)	↑ IOP ≥10 mm Hg) n = 0 for LE n = 1 (1.0%) for vehicle	≥1 AE: 54 vs. 75% (P = 0.002) 4 patients (all in vehicle group) discontinued due to AEs 1 patient in LE group hospitalized due to itching of arms, legs, and trunk; fatigue; and leg cramps
[55]	Postoperative cataract surgery with intraocular lens implantation; 2 weeks; LE 0.5% ointment QID (n = 404) vs. vehicle QID (n = 401) [2 studies]	(i) Resolution of ACI at day 8: 27.7 vs. 12.5% (P < 0.0001) (ii) Grade 0 (no pain) at day 8: 75.5 vs. 43.1% (P < 0.0001) (iii) Need for rescue medication: 27.7 vs. 63.8% (P < 0.001)	↑ IOP (≥10 mm Hg): n = 3 (0.7%) for LE n = 1 (0.2%) for vehicle Mean IOP decreased in both groups	≥1 ocular AE: 47.2 vs. 78.0% (P < 0.0001) Most common ocular AEs with LE were anterior chamber inflammation, photophobia, corneal edema, conjunctival hyperemia, eye pain, and iritis (all but corneal edema and photophobic, P < 0.05 vs. vehicle) ≥1 nonocular AE: 5.2 vs. 4.5% (P = NS) 3 subjects in vehicle group discontinued early due to a serious AE 1 serious ocular AE of cystoid macular edema in LE group No differences between treatment groups in visual acuity or dilated fundoscopy results Slit lamp results either comparable between treatment groups or favored LE
[58]	Postoperative cataract surgery with intraocular lens implantation; 2 weeks; LE 0.5% gel QID (n = 203) vs. vehicle QID (n = 203)	(i) Resolution of ACC at day 8: 30.5 vs. 16.3% (P < 0.001) (ii) Grade 0 (no pain at day 8): 72.9 vs. 41.9% (P < 0.001) (iii) Need for rescue medication: 42.4 vs. 71.9%	↑ IOP (≥10 mm Hg): n = 1 (0.5%) for LE; n = 1 (0.5%) for vehicle No significant difference between groups in mean change in IOP	≥1 ocular AE: LE – 18.7%; vehicle – 21.7% (P = NS) ≥1 drug-related ocular AE: LE – 4.4%; vehicle – 6.9% ≥1 nonocular AE: LE – 4.4%; vehicle – 4.4% (none considered treatment related) Treatment-emergent serious AEs: (i) 1 in LE group (cystoid macular edema) (ii) 3 in vehicle group (cystoid macular edema, bronchitis and exacerbated systolic congestive heart failure in same patient) No notable differences between treatment groups in visual acuity or dilated fundoscopy results Few patients in LE group had worsening ocular signs on biomicroscopy, and findings generally favored LE over vehicle
[59]	Postoperative cataract surgery with intraocular lens implantation; 2 weeks; LE 0.5% gel QID (n = 206) vs. vehicle QID (n = 201)	(i) Resolution of ACC at day 8: 31.1 vs. 13.9% (P < 0.001) (ii) Grade 0 (no pain at day 8): 75.7 vs. 45.8% (P < 0.001) (iii) Need for rescue medication, 30.1 vs. 61.2% (statistical significance not published)	↑ IOP (≥10 mm Hg): n = 0 for LE; n = 1 (0.5%) for vehicle	≥1 ocular AE: LE – 16.0%; vehicle – 28.9% (P = 0.002) ≥1 drug-related ocular AE: LE – 2.4%; vehicle – 7.5% ≥1 nonocular AE: LE – 5.8%; vehicle – 2.5% (P = NS; potential drug-related in LE group included facial rash and dry mouth) Serious AEs: (i) 3 in LE group (diverticulitis, cholecystitis, and myocardial infarction) (ii) 2 in vehicle group (dehydration and hypokalemia in same patient) With exception of change from baseline in visual acuity significant worse in vehicle group at Day 8 (P = 0.032), no notable differences between treatment groups in visual acuity or dilated fundoscopy results Few patients in LE group had worsening ocular signs on biomicroscopy, and findings generally favored LE over vehicle
[44]	Postoperative cataract surgery with intraocular lens implantation; 30 days; LE 0.5% suspension (n = 30) vs. ketorolac tromethamine 0.5% (n = 30); each QID for 1 week, then BID through 30 days	(i) Both treatments equally improved cell and flare, conjunctival inflammation graded by slit lamp (ii) Similar improvements in visual acuity	No between-group difference in IOP at any time point	No AEs reported in either group
[45]	Postoperative cataract surgery; LE 0.5% suspension (n = 48) or prednisolone acetate 1% (n = 45) QID for 3 weeks after surgery	(i) Control of inflammation was equivalent between treatment groups by assessment of cell and flare grading 1, 3, 7, and 21 days postoperatively	1 patient (2.2%) in the prednisolone group had ↑ IOP (≥10 mm Hg) 7 days after surgery considered drug-related; 2 patients (2.2%) had ↑ IOP (≥10 mm Hg) 1 day after surgery (treatment group not indicated) Mean change in IOP was numerically higher in the prednisolone acetate group than in the LE group (P = NS)	5 patients (3 [6.7%] prednisolone acetate group, 2 [4.2%] LE group) reported AEs during the course of the study
[63]	Phacoemulsification cataract surgery; difluprednate (n = 30 eyes) or LE gel (n = 30 eyes) QID for 3 days preoperatively; QID for 1 week postoperatively, then BID for 1 week	(i) Both treatments were equally effective in reducing inflammation (ii) Both treatment had a similar effect on postoperative visual recovery	At day 1 visit, ↑ IOP (≥10 mm Hg): n = 8 eyes (26.7%) for LE; n = 9 eyes (30.0%) for difluprednate; no patients with ↑ IOP at any other visit IOP changes were reportedly similar between the two treatment groups	↑ retinal thickness developed in 0 patients in LE group and 2 patients (6.7%) in difluprednate group
[46]	Photorefractive keratectomy; n = 62 patients; 1 eye of each assigned to LE 0.5% suspension or fluorometholone 0.1% for 3 months (QID month 1, TID month 2, BID month 3)	(i) Both treatments equally effective with regard to visual acuity, manifest refraction, corneal haze, ocular discomfort and redness (ii) No visually significant corneal haze in either treatment group	No ocular hypertension in either group (IOP rise of >10 mm Hg or IOP >21 mm Hg) No significant differences between groups in IOP elevation
[62]	Photorefractive keratectomy; n = 132 patients (261 eyes) randomized to: LE 0.5% gel (n = 114 eyes) QID for 1 week TID for 3 weeks BID for 1 month QD for 1 month OR Prednisolone 1% (n = 147 eyes) QID for 1 week BID for 3 weeks [Switch to fluorometholone] TID for 1 month BID for 1 month	(i) Similar incidence of haze (LE, 2.6% [3/114 eyes]; Prednisolone/fluorometholone, 4.8% [7/147 eyes]; P = 0.37) (ii) At 3 months, similar uncorrected visual acuity (LE, −0.078 ± 0.10; Prednisolone/fluorometholone, 0.075 ± 0.09; P = 0.83)	Clinically significant ↑ IOP (≥10 mm Hg over baseline or IOP >21 mm Hg): 1.8% (2/114 eyes) in the LE group; 4.1% (6/147 eyes) in the prednisolone group (difference not statistically significant)

ACI: anterior chamber inflammation; AE: adverse event; BID: twice daily; BKC: blepharokeratoconjunctivitis; IOP: intraocular pressure; LE: loteprednol etabonate; NS: not significant; QID: four times daily; tCSA: topical cyclosporine A; TID: three times daily.

^aN values represent patients unless indicated otherwise.

Adapted from [6] with permission of Hindawi.

4.1. LE suspension

4.1.1. Giant papillary conjunctivitis

Giant papillary conjunctivitis (GPC), an ocular allergic condition most often seen in contact lens (CL) wearers, is characterized by papillary hypertrophy, mucous discharge, itching, redness, and foreign body sensation [22]. Several clinical trials evaluated the use of LE 0.5% suspension for CL-associated GPC. In one double-masked 4-week trial, patients treated with LE 0.5% QID demonstrated significantly reduced papillae severity vs. vehicle as early as day 7 and at each weekly visit through the final visit on day 28 (all P ≤ 0.02) [23]. Patients in the LE group were given higher ratings in the investigator global assessment vs. placebo-treated patients (P = 0.017); patient ratings were not significantly different for LE vs. placebo, but favored LE. In two other similarly designed, double-masked studies, patients with GPC were assigned therapy with LE suspension 0.5% QID for 6 weeks while continuing CL use [24,25]. Both studies noted a significantly greater proportion of patients with an improvement in papillae of at least one severity grade among patients treated with LE vs. placebo (P ≤ 0.001) and a greater improvement in itching with LE vs. placebo (P ≤ 0.001). CL tolerance was marginally improved with LE in one study (P = 0.053) [25] and significantly improved in the other study (P = 0.002) [24] when compared with placebo. In these studies, transient increases in IOP of ≥10 mm Hg from baseline (considered clinically important) were noted in small percentages (3–7%) of LE-treated patients. It is likely that a reservoir effect from continued CL wear contributed to these IOP elevations.

4.1.2. Seasonal allergic conjunctivitis

Patients with seasonal allergic conjunctivitis (SAC) typically display symptoms of ocular itching, redness, and excessive tear production that can range from mild to severe [26]. Three double-masked placebo-controlled studies, each of 6-weeks duration, evaluated LE either as prophylaxis [27] or treatment [26,28] of SAC. In the prophylaxis study, LE 0.5% QID treatment was initiated prior to the allergy season (asymptomatic patients) [27]. Composite severity grades for itching and bulbar conjunctival injection (BCI) and investigator global assessments significantly favored LE 0.5% treatment (P ≤ 0.001) compared with placebo during periods of peak pollen counts. Two patients (1.4%; n = 143) in the placebo group had an IOP increase ≥10 mm Hg compare to none in the LE group (0%; n = 145). The efficacy of LE 0.2% QID in patients exhibiting ocular signs and symptoms of SAC was evaluated in 2 similarly designed studies [26,28]. In both trials, BCI and itching were reduced by a greater extent with LE compared with placebo at day 14 (P ≤ 0.034) and investigator global assessments at week 2 favored LE over placebo (P < 0.001). Across both studies, IOP elevations ≥10 mm Hg over baseline were noted in 1 (0.8%) LE-treated patient and 1 (0.7%) placebo-treated patient.

LE 0.2% suspension was compared with a dual-acting antihistamine mast-cell stabilizer, olopatadine HCl 0.1% solution, and with placebo for inhibiting early-phase allergic responses after conjunctival allergen challenge (CAC) in a double-masked, randomized study of 50 subjects with a history of allergic conjunctivitis [29]. Subjects in the LE study arm were treated with a 14-day ‘loading’ regimen (QID), while subjects randomized to olopatadine and placebo treatments received placebo QID for 14 days. On day 15, study medication was instilled 15 min prior to the CAC. At all 3 assessment time points (10, 15, and 20 min after challenge), improvements in itching and redness were better with olopatadine compared with LE (P < 0.05). Mean IOP in the LE 0.2% group increased from baseline (14.7 mm Hg) to 14 days (16.3 mm Hg) (P < 0.001). The authors acknowledged that a limitation of this study was its focus on the acute-phase reaction only rather than late-phase, in which corticosteroids are most effective.

Two environmental studies compared LE and olopatadine in patients with SAC, including a 2-week investigator-masked study in Chinese patients with SAC [30] which found LE 0.2% superior to olopatadine for improving BCI and ocular itching from baseline (P ≤ 0.0006). There were no clinically significant increases from baseline in IOP (≥10 mm Hg). In the other active-comparator study (also investigator-masked), Chinese children (ages 5–10 years) with SAC were randomized to bilateral treatment with olopatadine hydrochloride 0.1% twice a day (BID), emedastine difumarate 0.05% BID, LE 0.5% QID, or artificial tears (AT) for 14 ± 2 days [31]. On both days 8 and 15, all active treatments were found to be more effective than AT (P < 0.05) in reducing signs (conjunctival papillae, follicle, conjunctival congestion, edema) and symptoms (itching, photophobia, blinking) of SAC. However, no difference was observed among active treatments, possibly due to the sample size (n = 20 per treatment) and short duration of the study.

4.1.3. Vernal keratoconjunctivitis

Vernal keratoconjunctivitis (VKC) is a particularly severe form of ocular allergy which typically requires management with topical corticosteroids. The use of LE 0.5% was compared against PA 1% or fluorometholone 0.1% in an investigator-masked randomized study, each administered QID for 28 days [32]. Based on the evaluation of major signs and symptoms of VKC (itching, redness, tearing, foreign body sensation, burning, hyperemia, chemosis, Trantas dots, and corneal pannus formation, each graded 0 [none] to 3 [severe]), LE and PA produced similar and significant (P < 0.001) improvement from baseline, and both were better (P < 0.01) than fluorometholone for all measures except chemosis. Mean IOP was significantly elevated in the PA group only (Week 1 through Week 4).

4.1.4. Anterior uveitis

LE 0.5% was compared with PA 1% for the treatment of acute anterior uveitis in two randomized, double-masked studies [33]. In one study, both treatments were instilled 8 times per day for the first week, 6 times per day for the second week, QID for the third week, and then tapered according to the severity of the uveitis up to a total of 42 days of treatment. In the second and shorter study, treatment started with hourly administration (up to 16 times daily) for the first week, then every 2 h (up to 8 times per day) for the second week, QID for the third week, finally tapering down to QD by day 28. In each study, LE and PA both substantially reduced signs (anterior chamber cell [ACC] and flare) and symptoms (pain, photophobia) of uveitis from baseline to 28 days. In study 1, no statistical differences were observed between LE and PA in the proportion of patients with resolution of ACC, flare, pain, and photophobia by the last on-treatment visit (last observation carried forward) and at each individual study visit. In the second and larger study, more patients achieved resolution of cell and flare by the last visit (last observation carried forward) with PA compared with LE (P ≤ 0.017); however, there were no significant differences between treatments noted at individual study visits. Numerically but not statistically, greater percentages of patients experienced resolution of pain and photophobia with LE as compared to PA. Across both studies, IOP increases ≥10 mm Hg over baseline were noted in 1 (0.8%) LE- and 7 (5.6%) PA-treated patients.

4.1.5. Dry eye disorders

LE has been studied as a treatment for a variety of dry eye disorders [34–36], as well as induction therapy to reduce stinging associated with topical cyclosporine therapy for dry eye disease [37,38]. A 1-month randomized, double-masked, vehicle-controlled pilot study assessed the efficacy of LE suspension 0.5% QID in patients with dry eyes related to delayed tear clearance [34]. The primary objective variable, composite corneal staining, did not improve significantly with either treatment, while the primary subjective variable, severity of worst baseline symptom (visual analog scale), improved similarly from baseline in both groups (P < 0.0001). Among a cohort of patients with moderate or worse inflammation associated with dry eye, significant differences (P < 0.05) were noted at some visits in central corneal staining, nasal bulbar conjunctival hyperemia, and lid margin injection between the LE- and vehicle-treated groups. There were no instances of clinically significant IOP elevations during the month-long treatment.

A randomized, controlled, investigator-masked trial evaluated tear cytokine levels and clinical outcomes in patients with meibomian gland dysfunction (MGD) treated BID with eyelid scrubs and warm compresses alone or in combination with LE QID for 2 months [35]. The group using adjunctive LE demonstrated greater improvements from baseline in almost every clinical outcome evaluated, including TBUT, ocular surface epitheliopathy (staining), eyelid margin abnormality, meibum quality, expressiblity, ocular irritation, and MGD stage compared with eyelid scrubs and warm compresses alone (P < 0.05). The group using adjunctive LE also demonstrated significantly lower levels of the interleukins IL-6, IL-8, and IL-1ß (all P < 0.05 vs. non-LE group). There were no significant IOP increases in either group.

A prospective, randomized trial compared LE with topical cyclosporine 0.5% emulsion (tCSA) to prevent and treat graft versus host disease-related dry eye syndrome (DES) in patients undergoing hematopoietic stem cell transplant [36]. Patients were randomized to LE 0.5% BID or tCSA 0.05% BID starting 1 month before transplantation. After 12 months, rates of DES incidence and progression were similar between the two groups (P = 0.22 and P = 0.41, respectively; log-rank test). Kaplan–Meier analysis revealed a numerically lower rate of new DES development in the LE versus the tCSA group (79 vs. 90%), as well as a numerically lower rate of DES progression among patients who had DES at the beginning of the study (26 vs. 38%). There were no IOP elevations ≥10 mm Hg above baseline.

While tCSA (Restasis®) is indicated and effective for keratoconjunctivitis sicca (dry eye) patients [39], stinging is a common and sometimes treatment-limiting adverse reaction [40]. A retrospective analysis assessed clinical signs and symptoms and medication tolerability of patients who received LE 0.5% BID for 2–16 months prior to tCSA therapy initiation for chronic dry eye disease (CDED) compared with patients who did not receive LE induction therapy [38]. Of 36 patients in the induction therapy group, 2 (5.5%) reported significant stinging, leading to discontinuation in 1 patient (2.8%). In the group that did not receive LE pretreatment, 8 (22%) developed stinging, leading to discontinuation in 3 (8.3%) patients. Between group differences were significant for severe stinging (P < 0.02) and for tCSA discontinuation because of severe stinging (P < 0.04). There were no significant IOP elevations in the LE induction group, defined as 2 consecutive visits with an IOP increase ≥6 mm Hg from baseline.

In a later double-masked study, patients with CDED were randomized to treatment with either LE (n = 61) or AT (n = 57) QID for 2 weeks, followed by tCSA BID coupled with initial therapy (LE or AT) BID for 6 more weeks [37]. Compared to the AT group, patients using LE pretreatment experienced significantly less stinging on initial tCSA instillation (P < 0.05). In both treatment groups, Ocular Surface Disease Index (OSDI) outcomes improved significantly, but this was achieved earlier with LE (15 days) compared with AT (45 days). The LE group, but not the AT group, demonstrated significant improvements in other outcomes at day 60 (Schirmer test, central corneal staining, lissamine green staining). Mean IOP was not significantly increased in either group.

4.1.6. Postoperative inflammation following cataract surgery

The efficacy and safety of LE suspension 0.5% for the management of postoperative inflammation were assessed in two identical randomized, double-masked, vehicle-controlled trials in patients having cataract surgery with IOL implantation [41,42]. In both studies, patients instilled LE 0.5% suspension or vehicle starting the day after surgery, QID for 14 days. Resolution of anterior chamber inflammation was greater with LE compared with vehicle (P < 0.001) in both studies. Based on pooled findings for pain resolution, a greater percentage of LE-treated patients reported no pain at the final visit compared with vehicle-treated patients (84 vs. 56%; P < 0.05) [43]. Following surgery, mean IOP decreased in both groups. Three patients in the LE group (1.4%) experienced an IOP elevation ≥10 mm Hg, all of which resolved and one of which was related to uveitis.

A randomized, double-masked study compared LE 0.5% suspension and the non-steroidal anti-inflammatory ketorolac tromethamine 0.5% in 60 patients undergoing routine phacoemulsification with posterior chamber IOL implantation [44]. Starting on postoperative day 1, study medication was instilled QID for one week then BID through Day 30. There were no observed differences between treatments for any signs or symptoms of postoperative inflammation, and no difference in mean IOP.

In an investigator-masked, comparative case series, the efficacy of LE 0.5% suspension versus PA 1% suspension was evaluated for the control of postoperative inflammation in patients undergoing routine cataract surgery [45]. Patients were randomized to receive LE or PA QID for 3 weeks after surgery, as well as bromfenac 0.09% BID and besifloxacin 0.6% QID for 2 weeks after surgery. Based on 3-week postsurgical assessments of visual acuity, IOP, and ACC and flare intensity findings, the authors concluded that LE and PA provided similar levels of inflammation control, but that LE resulted in less IOP fluctuation.

4.1.7. Photorefractive keratectomy

Topical corticosteroids are often used to mitigate corneal haze and myopic regression following photorefractive keratectomy (PRK). In an investigator-masked study involving 62 patients undergoing PRK, patients were randomly assigned to treatment with LE 0.5% in one eye and fluorometholone in the other eye following surgery, each instilled QID for one month, then tapered to three times a day (TID) and BID during the next 2 months [46]. Three months postoperatively, there was no significant corneal haze noted and no significant differences between treatment groups in any other assessments: visual acuity, manifest refraction, IOP, or ocular discomfort/redness after drug instillation.

4.2. Combination LE/tobramycin suspension

LE 0.5%/tobramycin 0.3% ophthalmic suspension (LE/T) is indicated for inflammatory ocular conditions where superficial bacterial ocular infection or a risk of bacterial ocular infection exists. Two investigator-masked studies compared LE/T with dexamethasone 0.1%/tobramycin 0.3% (DM/T) suspension in patients with blepharokeratoconjunctivitis (BKC), each administered QID for 2 weeks [47,48]. In both studies, both combinations markedly improved the signs and symptoms of BKC from baseline to day 14, with no significant differences between treatments. In one study, IOP increased 5–9 mm Hg from baseline in 7.1% of 136 LE/T-treated patients and 14.4% of 137 DM/T-treated patients; additionally, one patient (0.7%) in the DM/T group had an IOP increase from baseline of ≥10 mm Hg [47]. In the other study [48], mean IOP was higher at all three follow-up visits in DM/T-treated versus LE/T-treated patients (all P ≤ 0.0186). Twice as many DM/T-treated patients developed IOP increases ≥10 mm Hg compared with LE/T-treated patients (7.3 vs. 3.4%; P = 0.0958); one case of IOP elevation ≥30 mm Hg was noted in the DM/T group [48]. A subsequent pooled analysis of data for blepharitis signs only from these two trials [49] found LE/T was effective in lessening blepharitis severity, with full resolution of signs in approximately half of patients after 15 days of treatment. While LE/T and DM/T demonstrated similar efficacy, LE/T appeared to have a clear safety advantage with regard to IOP response.

One additional randomized, double-masked study compared LE/T and DM/T in 40 patients with BKC, using shorter (3–5 days) and reduced (BID) dosing [50]. Severity scores evaluated after 3–5 days of treatment indicated greater improvement (lower severity) of symptoms with DM/T compared with LE/T for ocular surface (1.8 vs. 3.4), blepharitis (0.9 vs. 1.35), discharge (0.2 vs. 0.6), and conjunctivitis (0.15 vs. 0.6) (all P ≤ 0.025). Corneal punctate epithelial keratopathy severity improved in both treatment groups but was not significantly different between treatments at post-treatment assessment. No AEs were reported and no differences were observed in IOP findings between treatments. These findings should be interpreted cautiously, given the reduced dosing and short duration of treatment with both combinations.

Two randomized, multicenter, double-masked, parallel-group safety studies of LE/T were conducted in pediatric subjects aged 0–6 years [51]. In the first study, 108 pediatric subjects with lid inflammation (blepharitis) were treated with warm compresses BID 2 weeks along with LE/T or vehicle (QID for the first week and BID for the second week). In the second study, 137 subjects were randomized to LE/T, LE, tobramycin, or vehicle instilled QID for 14 days for blepharoconjunctivitis. Few ocular AEs, none serious, were reported during either study, and the investigators concluded LE/T appeared safe when used short term in pediatric subjects.

In a retrospective study, medical records were compared for 40 post-strabismus surgery patients who were managed postoperatively with LE/T (n = 20) or DM/T (n = 20) TID for 3 weeks [52]. There were no statistical differences between treatment groups for assessments of discomfort, chemosis, conjunctival hyperemia, or conjunctival gap size, and IOP measurements were within normal limits for both groups at all time points.

4.3. LE ointment

A preservative-free LE ointment 0.5% formulation became available in 2011. Ointment formulations may be beneficial for patients with tremors or arthritis as well as others who may have trouble instilling drops into their eyes [53], and remain on the ocular surface significantly longer than ophthalmic solutions, making them particularly suitable for nighttime use [54].

The use of LE ointment 0.5% QID over 2 weeks for the management of post-cataract surgery pain and inflammation was evaluated in 2 randomized, double-masked, vehicle-controlled studies (N = 805) [55]. In an analysis of pooled data from the two studies, findings at Day 8 revealed complete resolution of anterior chamber inflammation and absence of pain in significantly more LE-treated patients compared to vehicle-treated patients (both P < 0.0001). Rescue medication use and ocular AEs occurred in fewer patients treated with LE compared with those who received vehicle. With both treatments, mean IOP decreased from baseline, with no significant difference in IOP increases ≥10 mm Hg between the LE (n = 3, 0.7%) and vehicle (n = 1, 0.2%) groups.

Pterygium, an exposure-related eye disease, is a wing-shaped growth that extends from the bulbar conjunctiva onto the cornea. They typically, but not exclusively, occur on the nasal side, and can be unilateral or bilateral [56]. Excision is indicated in cases with compromised vision. In a published review of the role of LE ointment as part of post-pterygium surgery management, the authors concluded that LE ointment is safe and effective for this indication [56]. At present, there have been no prospective clinical studies of LE post-pterygium surgery.

4.4. LE gel

The latest formulation of LE 0.5% is a non-settling gel first marketed in 2012. The gel has a unique rheological nature that allows it to be instilled as a viscous drop, after which it transitions to a fluid state on the surface of the eye, and also contains polycarbophil, a mucoadhesive polymer designed to prolong ocular surface retention time. LE was detected in tear fluid for 24 h following gel instillation in both rabbits and human volunteers [17]. LE gel has a homogenous composition, and, compared with LE suspension, a lower concentration of the preservative benzalkonium chloride (0.003% vs. 0.01%), a more physiologic pH, (6.5 vs. 5.5) and does not need to be resuspended by shaking prior to administration [57].

The safety and efficacy of LE gel in the treatment of postoperative inflammation and pain following uncomplicated cataract surgery were demonstrated in two randomized, double-masked placebo-controlled clinical trials [58,59]. Patients were randomized to LE 0.5% gel or vehicle QID for 14 days following surgery. In an integrated analysis of 813 patients involved in these studies, significantly more LE gel-treated patients showed complete resolution of ACC and reported being pain free at postoperative days 8 and 15 compared to vehicle-treated patients (P < 0.001) [60]. Across both studies, transient IOP increases ≥10 mm Hg occurred in 2 (4.9%) LE-treated patients and 1 (2.5%) vehicle-treated patient [60]. Other side effects were typically mild to moderate and reported less frequently with LE gel than with vehicle.

The postoperative use of LE gel 0.5% (most commonly prescribed QID for 7–14 days) following laser-assisted in situ keratomileusis (LASIK) or PRK surgery was evaluated in a retrospective study. This study demonstrated that the gel was safe and effective for patients undergoing these procedures [61]. No increase from baseline in mean IOP was observed in either LASIK or PRK eyes postoperatively (P ≥ 0.33), and IOP elevations ≥10 mm Hg were observed in only 2 of 108 PRK patients (1.9%). More recently, LE 0.5% gel was evaluated in an investigator-masked study in 132 patients (262 eyes) undergoing PRK randomized to one of the following regimens: (1) LE 0.5% gel QID for the first week, TID for three weeks, BID for one month, then QD for one month; or (2) PA 1% QID for one week, then BID for three weeks, then switched to fluorometholone 0.1% suspension given TID for one month, BID for one month, then stopped [62]. Over the 3-month postsurgical follow-up, the incidence of haze was similar between the LE (2.6%) and PA/fluorometholone (4.8%) groups (P = 0.43). Refractive outcomes were considered excellent in both groups, and mean postoperative logMAR uncorrected visual acuity was similar between groups. Clinically significant IOP increases (≥10 mm Hg over baseline or any IOP >21 mm Hg) occurred in a smaller, albeit not significantly, percentage of eyes treated with LE (1.8%) vs. PA/fluorometholone (4.1%).

LE gel 0.5% (n = 30) was compared with difluprednate 0.05% (n = 30) for decreasing inflammation and improving vision recovery after phacoemulsification cataract surgery in an investigator-masked study [63]. All patients instilled assigned medication QID 3 days preoperatively and one week postoperatively, then BID for one week. Both treatments reduced inflammation equally and postoperative visual recovery was similar between treatments (P > 0.05). Although significant IOP elevations (≥10 mm Hg from baseline and ≥21 mm Hg) were noted 1 day after surgery in 30.0% of difluprednate and 26.7% of LE patients, all IOPs returned to baseline by the 1-month visit, and there was no difference in mean IOP between groups during the study. Patients with baseline IOP >21 mm Hg or vision-compromising ocular pathology were excluded from this cataract study.

The use of LE gel 0.5% was compared with PA 1% after Descemet membrane endothelial keratoplasty (DMEK) for the purposes of preventing corneal transplant rejection [64]. A total of 167 patients (233 eyes) were treated with PA 1% QID for the first postoperative month, at which point they were randomized to LE gel 0.5% or continued use of PA for the next 11 months. Both treatments were administered QID during the second and third months, TID during month 4, BID in month 5, and QD until the end of month 12. There were no immunologic rejection episodes in either treatment group. IOP elevations (IOP ≥24 mm Hg or increase of ≥10 mm Hg over the preoperative baseline level) occurred more than twice as often in the PA group than in the LE group (25 vs. 11%; P = 0.013).

LE gel 0.5% appeared safe and effective for dry eye in a small, exploratory study where patients with mild or moderate dry eye were randomized to one of three treatments: LE gel BID for 12 weeks (n = 36), LE gel BID for weeks 1–4 with the addition of tCSA BID for weeks 3–12 (n = 33), or tCSA BID for 12 weeks (n = 33) [65]. All three treatments reduced signs (fluorescein and lissamine green staining, tear film breakup time [TFBUT], Schirmer score) and symptoms (OSDI, DEQ-5, Comfort Index) of dry eye relative to baseline after 12 weeks (P < 0.05). At week 2, LE gel plus tCSA showed a treatment benefit versus tCSA alone for improvement from baseline in total OSDI (P = 0.022), while LE gel alone and LE gel plus tCSA showed a treatment benefit versus tCSA for OSDI visual function domain questions 6–9 (P ≤ 0.041). At week 4, treatment differences were noted in favor of LE gel versus tCSA for hyperemia (by keratography) and TFBUT (P ≤ 0.04). One patient each in the LE and LE plus tCSA groups had an IOP >21 mm Hg, both at week 12.

In an open-label study, 30 patients with MGD and evaporative dry eye were treated with LE gel 0.5% BID for 30 days [66]. At the end of treatment, TFBUT increased by 44.3% (P = 0.005). Other findings included a 52% decrease in corneal staining (P = 0.006), a 47.5% decrease in conjunctival staining (P = 0.002), a 31.9% decrease in MGD signs (P < 0.001), and a mean improvement in OSDI of at least 1 severity level (P = 0.004).

5. IOP effects

While topical ocular corticosteroids have undisputed benefits with regard to managing ocular inflammation, elevated IOP is a class concern. Published data on the effects of short-term (<28 days duration) and long-term (28 days up to 2 years duration) LE use on IOP were recently reviewed [67]. Pooled short-term data demonstrated a cumulative incidence of clinically significant IOP elevations (≥10 mm Hg from baseline) of 0.8% (14/1725 subjects); among long-term studies, the cumulative incidence was 1.5% (21/1386 subjects). Analysis of pooled data from controlled studies found a similar rate of clinically significant IOP elevation with LE versus vehicle [0.6% (9/1407) vs. 0.4% (6/1365); P = 0.646], but significantly lower rates compared with PA [3.4% (10/291) vs. 11.3% (33/292); P < 0.001] and compared with DM/T [1.8% (9/491) vs. 5.2% (25/485), P = 0.008] (Figure 3).

Figure 3. Cumulative rates of clinically significant IOP elevation in head-to-head studies (Reproduced from [67] with permission of Springer Nature).

The proportion of subjects with IOP elevation ≥10 mm Hg from baseline in studies of LE suspension and gel formulations compared to vehicle (10 studies) or PA 1% (5 studies) and of LE/T vs. DM/T (4 studies). *P < 0.01 vs. comparator, DM/T dexamethasone 0.1%/tobramycin 0.3% suspension, LE loteprednol etabonate, LE/T loteprednol etabonate 0.5%/tobramycin 0.3% suspension, IOP intraocular pressure, PA prednisolone acetate.

Studies in known steroid responders have confirmed that LE has a low propensity for eliciting IOP elevations in this high-risk population [68,69]. Bartlett et al. conducted a double-masked, randomized, cross-over study in 14 known steroid-responders treated with either LE 0.5% suspension or PA 1% QID for 42 days and then crossed-over to the other treatment after a washout period. Treatment with LE did not significantly impact mean IOP over the study, while PA resulted in a significant mean IOP elevation at each post-baseline visit [68]. Holland retrospectively reviewed 30 post-penetrating keratoplasty and post-keratolimbal allograft patients who, after having an IOP increase with PA 1%, demonstrated a reduction in IOP after switching to LE 0.5% suspension with continued treatment for a median period of 20 weeks [69].

6. Cataract formation

Manabe and colleagues demonstrated that PA and other C-20 ketone steroids can form covalent bonds, or adducts, with lens protein, whereas nonketolic analogs are unable to form such adducts [14]. Because LE was designed with an ester rather than a ketone group at the C-20 position, its chemical structure is not conducive to forming such covalent adducts. However, it is possible that other, or as yet unknown, corticosteroid-induced mechanisms of cataractogenesis exist [2].

A study that assessed the long-term safety (>12 months) of LE 0.2% (given once to 4-times/day) in the treatment of seasonal and perennial allergic conjunctivitis did not suggest a potential for cataract formation even after more than 36 months of follow-up in some patients [70]. A review of global postmarketing AE data reported through October 2016, reflecting an estimated distribution of 85 million units of LE, revealed 12 voluntary reports of cataract formation in patients using LE (any formulation) since 1998, although causality cannot be established by such reports [71].

7. Conclusions

The principles of retrometabolic drug design were applied in the development of LE, a corticosteroid with a C-20 ester which replaces the C-20 ketone that is characteristic of PA. This substitution, as well as the 17α-etabonate moiety, makes possible the necessary balance between in vivo solubility and lipophilicity, distribution into ocular tissues, binding to the GR, and the rate of de-esterification into an inactive metabolite. Preclinical and clinical studies confirm that LE is a safe and effective option for the treatment of a number of ocular inflammatory conditions including GPC, SAC, anterior uveitis, blepharokeratoconjunctivitis, keratoconjunctivitis sicca, and postoperative pain and inflammation therapy following PRK, LASIK, and cataract surgery with IOL implantation. In the pediatric population, LE has been shown to be safe for short-term therapy in patients 0–6 years of age with blepharitis and blepharoconjunctivitis. The substantial volume of data accumulated over the past two decades provides clinical evidence that the retrometabolic design of the LE molecule has, in fact, resulted in a compound that is clinically effective but with a lower propensity to cause AEs seen with other ocular corticosteroids, notably IOP elevation and cataract formation.

8. Expert opinion

Steroids remain the most potent topical, injectable, depot implantable, and systemically administered pharmaceutical agents available for controlling ocular inflammation, and LE appears to one of the safest in the entire class. The combination of efficacy and safety often renders a ‘smart steroid’ designation, while efficacy purported to be less than other steroids such as difluprednate somewhat inaccurately recalls the ‘soft steroid’ moniker, a label originally coined to reflect better safety. In reality, as demonstrated in both tightly controlled animal model experiments and human trials, LE performs with admirable potency for a variety of indications compared to other topical steroids [20,33,45,47–50,52,62–64], the nonsteroidal anti-inflammatory ketorolac [44], and tCSA [36,65]. However, the rapid metabolism responsible for the improved safety of LE could result in slightly lower efficacy relative to other corticosteroids in cases of particularly severe, acute inflammation as suggested by one of two studies in acute anterior uveitis [33]. Enhanced drug delivery with submicron [72] or mucus-penetrating [73] LE particles may, in the future, increase the ocular penetration and thus potential efficacy of a given concentration of topical LE.

Promising investigational chemical entities including SEGRAs (selective GR agonists) [74] and aldehyde trap strategies [75] target the enviably established combination of efficacy and safety enjoyed by LE, but their approval awaits additional randomized, controlled human trial data. Although safety has always been the premier LE asset, versatility bespeaks a deep portfolio in clinical practice. LE has become a preferred ocular surface anti-inflammatory agent for a multitude of acute and chronic conditions seen routinely in comprehensive ophthalmology, primary care optometry as well as referral corneal external disease practices. For numerous clinicians, LE is a favored agent for more severe and chronic forms of ocular surface disease, including blepharitis, dry eye and allergy, particularly when multiple etiologies converge upon the same patient and chronic therapy is indicated. Personalized medicine and genomic profiling may provide considerable foresight regarding efficacy and safety for any anti-inflammatory class prior to prescription, further refining medication selection as well as permitting higher doses for appropriate patients and organ targets.

For surgical patients with preexisting ocular surface disease, elevated IOP, so-called steroid responders, and candidates with cataract and glaucoma anticipating MIGS (micro-incisional glaucoma surgery), LE very often rises to most preferred agent. With the perceived enhanced potency of gel and ointment formulations, many surgeons and their management teams are also recommending off-label reduced frequency regimens, or more rapid medication weaning when compared to the suspension formulation.

Finally, LE works hand in hand with partnered pharmaceuticals to create clinically viable induction and maintenance strategies. In dry eye, LE becomes the initial fast onset potent agent for induction therapy, followed by long term prescription tCSA maintenance therapy [37]. Many patients with controlled chronic anterior uveitis patients benefit from continuous low-dose LE maintenance therapy to avoid recurrent attacks following treatment of acute disease with a different topical steroid. Thus, LE versatility is expressed by numerous clinical indications, a diverse spectrum of responsive disease states, targeted therapy for numerous commonplace and niche surgical procedures, as well as applicability for both initiation and maintenance therapy. More than two decades after first approval, LE remains a mainstay for eye care providers and a balanced treatment solution for patients.

Article highlights

• Loteprednol etabonate (LE) is a topical ophthalmic corticosteroid retrometabolically engineered to undergo rapid local metabolism into inactive metabolites with the goal of improved safety, including a lower risk of elevated intraocular pressure (IOP), relative to other ocular corticosteroids.

• Preclinical research confirmed a high level of corticosteroid-related efficacy and potency with LE, along with low aqueous humor concentrations of unmetabolized drug and little evidence of IOP elevation in animal models.

• Over the past two decades, a large body of clinical research has accumulated with various formulations of LE which include a suspension, an ointment, a combination product with tobramycin, and a recently introduced gel.

• Clinical studies have demonstrated the effectiveness of LE in various ocular inflammatory diseases (giant papillary conjunctivitis, seasonal allergic conjunctivitis, vernal keratoconjunctivitis, anterior uveitis, blepharokeratoconjunctivitis, dry eye disorders) and for control of postoperative inflammation and pain following cataract surgery and refractive surgeries.

• The risk of clinically significant IOP elevation with LE has been shown to be low (similar to that observed with vehicle) and significantly less than with other ocular corticosteroids, even in patients known to be steroid responders.

• Based on extensive experience accumulated over the past two decades, combined with the clinical flexibility offered by various formulation options, LE has become a trusted and versatile ophthalmic corticosteroid option.

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Declaration of interest

TL Comstock and JD Sheppard are paid consultants for Bausch & Lomb Incorporated and have designed and/or participated as an investigator in several LE preclinical and/or clinical studies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript and funded by Bausch & Lomb Incorporated. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

S Westra and R Gasbarro of Churchill Communications are thanked for their writing assistance with this manuscript. We also thank M Cavet and H DeCory of Bausch & Lomb Incorporated for assisting in the review of the manuscript for accuracy and completeness.

Additional information

Funding

This manuscript was funded by Bausch & Lomb Incorporated.