As indicated previously, while the efficacy of topical ocular corticosteroids in the treatment of ocular inflammation has been shown, they also have the potential of increasing IOP [
1,
11,
13,
15,
16,
19,
27‐
31]. However, to date, meaningful comparisons of the potential for corticosteroid-induced increase in IOP with different corticosteroids have been hampered by a lack of a standard format for testing and reporting clinically significant IOP elevations [
18]. In the mid-1960s, Becker used absolute IOP as the criterion, with 20 mmHg being the lower limit of a clinically significant response, while Armaly [
32,
33] classified the IOP response as a relative difference (treated vs. untreated eye), with a difference of 6 mmHg being the lower limit of a clinically significant response. In 1984, Stewart et al. [
34] conducted a study comparing the ocular pressure effects of fluorometholone acetate and dexamethasone sodium phosphate in steroid responders, and proposed that an increase in IOP of ≥10 mmHg over baseline should be considered clinically significant. This value was readily accepted by the ophthalmic community; it has since been adopted by the United States FDA, and many subsequent studies have associated an increase in IOP of ≥10 mmHg over baseline with clinical significance [
2,
4,
5,
35‐
40]. Nonetheless, many relatively recent studies still fail to report this outcome. Below, we review published studies on topical ophthalmic corticosteroids used in post-operative inflammation, noting any reports of IOP elevations of ≥10 mmHg where available.
Older Corticosteroids
Because early generation corticosteroids, including dexamethasone, prednisolone, and fluorometholone, were introduced prior to current regulatory requirements, pivotal placebo-controlled clinical trials are lacking. However, a few recent comparative studies were found in the literature and provide an insight to their IOP effects.
Saari et al. [
41] compared the anti-inflammatory effects of 0.7% dexamethasone-cyclodextrin aqueous solution instilled once daily and 0.1% dexamethasone sodium phosphate instilled three-times daily in 20 patients undergoing cataract surgery. Patients were randomized to receive study treatment post-operatively and were assessed on post-operative days 1, 3, 7, and 21. Laser flare cell meter measurements showed that on post-operative day 21 patients treated with 0.7% dexamethasone-cyclodextrin demonstrated lower mean post-operative photon count and mean cell count (
P ≤ 0.032) than those treated with dexamethasone sodium phosphate. No significant differences in the mean [standard deviation (SD)] IOP were observed between treatment groups [14.0 (3.1) vs. 14.3 (2.1) mmHg at final visit] [
41]. However, IOP elevations of ≥10 mmHg over baseline were not reported. Laurell and Zetterstrom [
30] compared the effects of treatment with dexamethasone, diclofenac, or placebo in 180 patients after phacoemulsification and intraocular lens (IOL) implantation. Inflammation was measured by laser flare photometry pre-operatively and at 1, 3, and 8 days, 2 and 4 weeks, 2 and 6 months, and 1, 2, and 4 years post-operatively. Dexamethasone and diclofenac were more efficacious than placebo and were equally efficacious in the reduction of post-operative inflammation. At post-operative day 8 and 1 month, a significantly higher mean IOP was observed in the dexamethasone group when compared with the placebo group (16 vs. 13 mmHg at day 8, and 15 vs. 14 mmHg at 1 month, respectively;
P < 0.05 for both). The authors reported that no patient exhibited an increase in IOP of ≥10 mmHg [
30].
Lorenz et al. [
42] studied the effects of prednisolone acetate 0.5% on intraocular inflammation after phacoemulsification. Prednisolone acetate 0.5% or placebo was instilled in 62 patients four-times daily until day 2 post-operatively. All patients were then treated with open-label prednisolone acetate 0.5% administered four-times daily until day 14. A significant difference between prednisolone acetate and placebo was observed on post-operative day 3 in protein flare (20.8 vs. 32.6 photon counts/ms, respectively;
P = 0.0055) while flare measures were comparable at day 14 (13.0 and 11.4 photon counts/ms, respectively). Increased IOP (degree of increase not reported) was observed in three patients (4.8%), although mean IOP was considered normal (<21 mmHg) in both groups at the end of the treatment period [
42]. Smerdon et al. [
43] compared the efficacy and safety of prednisolone 0.5% with placebo (vehicle) in the control of inflammation following cataract extraction in 120 patients. Treatment with tolmetin 2% was included in the study as the third treatment arm. Treatments were administered four-times daily for 6 weeks. Resolution of post-operative inflammation was reported for a significantly higher proportion of patients in the prednisolone group compared to the placebo group (94% vs. 46%, respectively;
P < 0.001). Seven patients (24%) in the prednisolone group when compared with three patients (9%) in the placebo group had IOP elevated to >22 mmHg during the trial. However, the authors did not report whether any IOP elevations were ≥10 mmHg above baseline.
Our literature search failed to identify randomized, placebo-controlled studies of fluorometholone in post-cataract surgery. However, Trinavarat et al. [
44] compared the efficacy and adverse effects of prednisolone acetate 0.5%, ketorolac tromethamine 0.5% and fluorometholone acetate 0.1% in patients with post-operative inflammation following cataract surgery. A total of 120 eyes were enrolled in this prospective, investigator-masked, randomized controlled trial with each drug administered four-times daily for 4 weeks. All treatments were effective in the primary outcome measure—reducing inflammation after phacoemulsification. Mean IOP was higher in the prednisolone group when compared with the ketorolac group on day 21 (14.6 vs. 12.2 mmHg, respectively;
P = 0.016) but did not differ from the fluorometholone group (13.8 mmHg). One eye in the prednisolone group had an IOP of 32 mmHg on day 21 and was terminated from the study. Vetrugno et al. [
45] compared the efficacy and tolerability of fluorometholone 0.1% acetate and fluorometholone 0.2% in two groups of 30 patients who had undergone myopic photorefractive keratectomy. Patients instilled treatments four-times daily for 1 month, followed by treatment application at decreasing frequency every 3 weeks. No significant differences were observed in visual acuity, haze, and mean IOP between the two groups, although mean IOP increased relative to baseline in both groups. Three patients in the fluorometholone 0.2% group and two patients in the fluorometholone acetate 0.1% group had increased IOP at 15 and 30 days (fluorometholone 0.2% group: 28, 31, 26 mmHg; fluorometholone 0.1% acetate group: 27, 26 mmHg). The authors did not report whether any of these elevations were ≥10 mmHg over baseline, but indicated that IOP-lowering medication was administered.
While these studies demonstrate the efficacy of older corticosteroids for post-operative inflammation, safety findings suggest potential IOP effects with all three corticosteroids. The lack of consistent IOP reporting precludes more meaningful comparisons across these studies.
Newer Corticosteroids
Rimexolone, difluprednate, and loteprednol etabonate are relatively recent ophthalmic corticosteroids introduced during today’s more comprehensive regulatory environment. Hence, pivotal placebo-controlled clinical trials, as well as comparative trials for these steroids are available in the literature. Table
1 [
2‐
5,
40,
46‐
48] summarizes comparative rates of resolution of inflammation and clinically significant increases in IOP observed with each of these three newer corticosteroids in placebo-controlled trials.
Table 1
Resolution rates of post-operative inflammation and incidence of intraocular pressure elevation of ≥10 mmHg in placebo-controlled studies with rimexolone, difluprednate and loteprednol etabonate
Study drug | Rimexolone | Rimexolone | Difluprednate | Difluprednate | Loteprednol etabonate suspension | Loteprednol etabonate suspension | Loteprednol etabonate gel | Loteprednol etabonate gel |
Comparator | Placebo | Placebo | Placebo | Placebo | Vehicle | Vehicle | Vehicle | Vehicle |
Total patients randomized | 182 | 197 | 438 | 121 | 227 | 203 | 407 | 406 |
Primary efficacy parameter | Resolution of ACI | Resolution of ACI | Resolution of ACC and flare, and other ocular signs of inflammationa
| Resolution of ACC and flare | Resolution of ACI | Resolution of ACI | Resolution of ACC and grade 0 pain | Resolution of ACC and grade 0 pain |
Duration of study | 15 days | 15 days | 15 days | Treatment for 16 days, followed by a tapering period of 14 days | Up to 2 weeks | Up to 2 weeks | 2 weeks | 2 weeks |
Dosing schedule | 4 times a day | 4 times a day | 2 or 4 times a day | 2 times a day | 4 times a day | 4 times a day | 4 times a day | 4 times a day |
Proportion of patients with resolution of ACI/ACCb for study drug at final visit | Rimexolone: 50%; placebo: 21.1% | Rimexolone: 59.7%; placebo: 19.6% | Difluprednate 2 times daily: 55.4%; difluprednate 4 times daily: 63.1%; placebo: 15.7% | Difluprednate 2 times daily: 74.7%; placebo: 42.5% | LE: 64%; vehicle: 29% | LE: 55%; vehicle: 28% | LE: 31.1%; vehicle: 13.9% | LE: 30.5%; vehicle: 16.3% |
Patients with IOP elevations of ≥10 mmHg over baseline, n (%) | Not reported | Rimexolone: 2 (1.5%); placebo: 2 (3.2%) | Difluprednate 2 times daily: 3 (2.7%); difluprednate 4 times daily: 3 (2.8%); placebo: 2 (0.9%) | Difluprednate 2 times daily: 3 (3.7%); placebo: 0 (0.0%) | LE: 3 (2.7%); vehicle: 0 (0.0%) | LE: 0 (0.0%); vehicle: 1 (1.0%) | LE: 0 (0.0%); vehicle: 1 (0.5%) | LE: 1 (0.5%); vehicle: 1 (0.5%) |
Rimexolone is a highly lipophilic glucocorticoid that lacks a hydroxyl substituent at the 21-position of the core corticosteroid structure [
49,
50]. Foster et al. [
37] suggested that the lipophilicity of rimexolone results in a balance between efficacy and safety. Specifically, rimexolone is thought to achieve ocular tissue levels sufficient to treat inflammation, while its limited ocular penetration and biological half-life minimize any IOP effects [
37]. Bron et al. [
3] examined the efficacy and safety of a 2-week regimen of rimexolone 1% as compared to placebo in reducing post-operative inflammation in 182 post-cataract patients. The proportion of patients showing resolution of anterior chamber inflammation (ACI) was 50% and 21.1% for the rimexolone and placebo groups, respectively (
P = 0.0003), on post-operative day 15. Rimexolone-treated patients had significantly less bulbar conjunctival erythema, corneal edema, anterior vitreous reaction, and ocular discomfort (
P < 0.05). No perceptible changes in IOP were reported for either group, but the authors noted that the study was not designed to show differences in IOP response. Assil et al. [
46] also compared rimexolone to placebo for post-operative inflammation in 196 post-cataract patients. ACI was completely resolved in 59.7% and 19.6% of patients in the rimexolone and placebo groups, respectively, on day 15 post-operatively. There was no between-group difference in mean (SD) IOP on day 15 [15.7 (4.7) and 14.9 (3.3) mmHg in the rimexolone and placebo groups, respectively;
P = 0.32]. However, two patients in each group exhibited an increase in IOP of ≥10 mmHg over baseline.
Yaylali et al. [
51] compared the efficacy and safety of rimexolone 1% to prednisolone acetate 1% in 48 post-cataract patients. Treatments were administered four-times daily for 15 days post-operatively, and patients were examined on post-operative days 1, 3, 7, and 15. Anterior chamber cell and flare, and conjunctival hyperemia were the main efficacy parameters; IOP was assessed as a safety parameter. Across all efficacy parameters, rimexolone was equivalent to prednisolone acetate 1%, with the exception of mean (SD) number of anterior chamber cells at day 3 [0.55 (0.5) vs. 0.19 (0.40), respectively;
P = 0.01]. Post-operative IOP values were also similar between treatment groups, with the exception of day 3, on which the mean (SD) IOP was found to be higher in the prednisolone group [11.9 (1.9) vs. 10.9 (1.3) mmHg;
P = 0.038]. IOP increases ≥10 mmHg from baseline were not reported. Kavuncu et al. [
52] also compared the efficacy and safety of rimexolone 1% with that of prednisolone acetate 1.0%. Patients (
n = 80) undergoing cataract extraction with IOL implantation were randomized to receive either prednisolone acetate or rimexolone every 4 h for 18 days. There were no differences between treatments in anterior chamber cell count or flare. Treatment with rimexolone was associated with higher conjunctival hyperemia on days 1 and 3 (
P < 0.05), while treatment with prednisolone acetate was associated with higher corneal edema on day 8 (
P < 0.05). There were no between-treatment differences in the mean IOP at any visits, with IOP ranging from 11.1 to 14.0 and 10.5–14.7 mmHg in the prednisolone acetate and rimexolone groups, respectively.
Difluprednate, a derivative of prednisolone that is difluorinated at the C6 and C9 positions [
4], is approved for treating post-operative inflammation in the United States and some countries in the European Union. Originally developed for dermatologic applications, it was also found to rapidly penetrate the corneal epithelium [
4]. Korenfeld et al. [
4] compared the efficacy and safety of difluprednate ophthalmic emulsion 0.05% with that of placebo (vehicle) in 438 patients with inflammation after ocular surgery in two studies. Difluprednate and placebo were instilled twice daily in one study and four-times daily in the other. Both difluprednate regimens were effective in reducing pain and inflammation post-operatively as compared to placebo. The proportion of patients with resolution of anterior chamber cells (grade 0 cells) on day 8 was 30%, 35%, and 9% in the difluprednate group with the twice-daily dose regimen, difluprednate group with the four-times daily dose regimen, and the pooled placebo group, respectively (
P < 0.0001 vs. placebo for both difluprednate regimens). However, 3% of patients in both difluprednate groups exhibited an increase in IOP of ≥10 mmHg from baseline to an IOP of ≥21 mmHg as compared to 1% of patients in the placebo group. Smith et al. [
40] also compared the efficacy and safety of difluprednate ophthalmic emulsion 0.05% with that of placebo (vehicle) in 121 patients undergoing cataract surgery. In this study, dosing was initiated 24 h before surgery and consisted of twice-daily administration for 16 days, followed by a 14-day tapering period. Resolution of ACI (anterior cells grade, 0; flare grade, 0) on day 14 was higher among patients in the difluprednate group than in the placebo group (74.7% vs. 42.5%,
P = 0.0006). Again, three patients (3.7%) in the difluprednate group had an increase in IOP of ≥10 mmHg from baseline to an IOP of ≥21 mmHg as compared with none of the patients in the placebo group.
The IOP-increasing potential of difluprednate was further investigated by Cable in a retrospective chart review [
53]. Data from 100 consecutive, uncomplicated phacoemulsification patients treated with difluprednate ophthalmic emulsion 0.05% twice daily post-operatively were analyzed. Five percent of patients, all with a history of open-angle glaucoma, responded with ocular hypertension. The average increase in IOP among responders was 17.8 mmHg, considerably higher than the accepted value for a clinically significant increase (≥10 mmHg). Moreover, 60% of IOP elevations were noted on post-operative day 1 and a further 40% on post-operative day 7. The authors concluded that difluprednate administered twice daily could cause significant and early elevations in IOP.
Loteprednol etabonate is approved for the treatment of post-operative inflammation in the United States and most countries in the European Union. Loteprednol etabonate differs from other ophthalmic corticosteroids in that it has an ester rather than a ketone at the C-20 position of the core corticosteroid structure [
54]. Loteprednol etabonate was designed through retro-metabolic drug design; a process by which an inactive, non-toxic metabolite of a reference compound, in this case prednisolone, is chemically modified to a therapeutically active compound [
55,
56]. Clinically, following ocular penetration and saturation of the glucocorticoid receptor in ocular tissues, unbound loteprednol etabonate undergoes rapid de-esterification to its inactive metabolite, Δ
1 cortienic acid etabonate, or PJ-91, resulting in a decreased impact on IOP [
39,
56‐
58]. The efficacy and safety of loteprednol etabonate 0.5% suspension in post-operative inflammation were demonstrated in two placebo-controlled studies (
n = 227 and
n = 203, respectively) [
2,
5]. In both studies, patients were randomized to either loteprednol etabonate 0.5% or vehicle four-times daily for up to 14 days after cataract surgery. In the first study, ACI was resolved in 64% and 29% of patients in the loteprednol etabonate and vehicle groups, respectively; while in the second study, ACI was resolved in 55% and 28% of patients, respectively (
P < 0.001 for both studies) at post-operative day 15. A post hoc analysis of pooled data from both studies showed that pain was resolved in 84% and 56% of patients with baseline pain scores of >0 for the loteprednol etabonate and vehicle groups, respectively (
P < 0.05) [
59]. In both studies, there was an overall mean decrease in IOP of 1–2 mmHg for the loteprednol etabonate- and vehicle-treated patients at all post-operative visits relative to screening, with no significant differences between the treatment groups in either study. A clinically significant increase in IOP (≥10 mmHg) over baseline was observed in three patients in the loteprednol etabonate group in the first study and in one patient receiving the vehicle in the second study.
Lane and Holland compared the efficacy and safety of loteprednol etabonate 0.05% with that of prednisolone acetate 1.0% (Pred Forte
®, Allergan, Inc., Irvine, CA, USA), administered four-times daily in 88 patients following routine cataract surgery and found similar control of inflammation after surgery [
60]. At post-operative days 1, 3, 7, and 21, mean IOP and mean change in IOP were higher in patients treated with prednisolone acetate than in those treated with loteprednol etabonate, although this did not reach statistical significance. One patient in the prednisolone acetate treatment group had a clinically significant increase in IOP (≥10 mmHg) over baseline.
Fong et al. and Rajpal et al. [
47,
48] recently examined the efficacy and safety of a gel formulation of loteprednol etabonate as compared to vehicle (both dosed four-times a day) in reducing post-operative inflammation and pain in post-cataract patients (
n = 407 and
n = 406, respectively). The gel contains 0.5% loteprednol etabonate in a non-settling formulation intended to provide consistent dose uniformity without the need to shake. In both multicenter, randomized, masked studies a greater proportion of loteprednol etabonate-treated patients had complete resolution of anterior chamber cells on Day 8 as compared to vehicle-treated patients (31.1% vs. 13.9% and 30.5% vs. 16.3%, respectively;
P < 0.001 for both). Similarly, a greater proportion of loteprednol etabonate-treated patients had grade 0 pain (75.7% vs. 45.8% and 72.9% vs. 41.9%, respectively,
P < 0.001 for both). In both studies mean IOP was consistently lower than baseline for both treatment groups at follow-up visits. Two patients in the loteprednol etabonate-treatment group and one patient in the vehicle group exhibited a clinically significant increase from baseline in IOP (≥10 mmHg) across the two studies.
Low incidences of elevated IOP (≥10 mmHg) have also been observed in studies of loteprednol etabonate suspension in the treatment of giant papillary conjunctivitis, seasonal allergic conjunctivitis, anterior uveitis, and delayed tear clearance [
35,
61‐
64] or when loteprednol etabonate was used in combination with tobramycin in the treatment of blepharokeratoconjunctivitis [
65‐
68]. Novack et al. [
69] further examined the IOP data from all patients enrolled in loteprednol etabonate development trials in the United States who received treatment for a period of ≥28 days, and found that loteprednol etabonate had minimal effect on IOP when used long term. Of patients who received loteprednol etabonate 0.5% or 0.2%, 1.7% (15/901) exhibited IOP elevations of ≥10 mmHg over baseline as compared with 6.7% (11/164) of patients who were treated with prednisolone acetate 1.0%. Among patients using loteprednol etabonate 0.5%, only 2.1% (14/664) demonstrated clinically significant increases in IOP; this proportion was reduced to 0.8% (3/387) when patients who continued to wear contact lenses during treatment were eliminated, suggesting that contact lenses might potentially act as reservoirs for corticosteroids [
69].
Taken together, the above studies indicate that the newer corticosteroids, i.e., rimexolone, difluprednate, and loteprednol etabonate, offer similar efficacies in terms of resolution of post-operative inflammation. However, fewer clinically significant increases in IOP appeared to be associated with rimexolone and loteprednol etabonate use when compared with difluprednate use, likely due to ocular pharmacokinetic differences among these steroids. Further comparative studies are needed, however. The most clinical data on IOP effects was found for loteprednol etabonate and suggested little effect on IOP associated with loteprednol etabonate.