Summary Basis of Decision for Durezol

Clinical Pharmacology

Difluprednate (the medicinal ingredient of Durezol) is a glucocorticoid receptor agonist, a difluorinated derivative of prednisolone that has anti-inflammatory activity.

Difluprednate undergoes deacetylation in vivo to 6α, 9-difluoroprednisolone 17-butyrate (DFB), an active metabolite of difluprednate. Clinical pharmacokinetic studies of difluprednate (0.01% or 0.05%) after ocular instillation of 2 drops four times a day (QID) for 7 days showed that DFB levels in blood were below the quantification limit (50 ng/mL) at all time points for all subjects, indicating the systemic absorption of difluprednate after ocular instillation of Durezol is limited.

Based on two studies (one in adults and one in children), there was some evidence that dermally applied difluprednate could induce some suppression of the adrenocortical functions. This is relevant for chronic dermal application, and possibly not for ocular administration, especially short-term use (14 days, ± 14 days tapering). There was no evidence of clinically significant corticosteroid systemic effects following Durezol when administered 1 drop QID for 7 days. It is unlikely that the systemic effects of using Durezol for short term (14 days, ± 14 days tapering) may result in significant systemic impact.

Overall, the pharmacological data together with the clinical data support the use of Durezol for the specified indication.

For further details, please refer to the Durezol Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Durezol was demonstrated in four pivotal studies; two studies for the treatment of post-surgical inflammation and two for endogenous anterior uveitis.

Post-surgical inflammation

The two pivotal studies (Studies 002a and 002b) were randomized, double-blind, placebo-controlled, Phase III studies. A total of 219 patients with ocular inflammation following cataract surgery (anterior chamber cell count ≥11) were randomized to receive Durezol or placebo. Patients had no history of glaucoma, ocular hypertension, rise in steroid-related intraocular pressure (IOP), corneal abrasion/ulceration, and had an IOP <24 mm Hg on Day 1 after surgery. The patients received 1 drop, either twice a day (BID) or four times a day (QID) of Durezol, or placebo (starting one day after surgery), for 14 days followed by a tapering period of up to an additional 14 days. The primary efficacy endpoint was the proportion of patients with anterior chamber (AC) cell count = 0. The main secondary endpoint was the proportion of pain/discomfort-free patients.

The pooled data from both pivotal studies provided evidence that Durezol was efficacious in reducing inflammation and ocular pain in patients following cataract surgery. The efficacy results were calculated without using the Last Observation Carried Forward (wo/LOCF), and with the use of Last Observation Carried Forward technique (w/LOCF). After 8 days of Durezol QID, the proportion of patients with an AC cell count of 0 was statistically significantly larger with Durezol (22% wo/LOCF, 22% w/LOCF) as compared to placebo (10% wo/LOCF, 8% w/LOCF), with a statistically significant proportions difference of 14% wo/LOCF (15% w/LOCF). At Day 15, the benefit was more salient with a difference in proportions of 25% wo/LOCF (30% w/LOCF) in favour of Durezol. In both studies, the efficacy results were statistically significant when LOCF was used. When LOCF was not used, Durezol superiority was also statistically significant except for Day 8 in Study 002a where the difference in rates between treatment groups was not significant (11%, p=0.09). This was considered acceptable, as this single discrepancy between findings with LOCF versus (vs.) without LOCF was deemed probably related to the higher rate of patient withdrawal due to lack of efficacy in the placebo group. In addition, the pooled results were clearly in favour of Durezol with statistical significance at Day 8 and 15. The results based on the per-protocol (PP) dataset were generally in line with those using the intent-to-treat (ITT) population.

The proportion of pain-free patients was significantly larger with Durezol as compared to placebo in both studies at Day 8, with or without the use of LOCF. At Day 15, the differences in pain resolution rates were also all statistically significantly in favour of Durezol, except for Study 002b without LOCF. This single minor discrepancy in the findings with LOCF vs. without LOCF was possibly related to the higher rate of patient withdrawal in the placebo group due to lack of efficacy. In the pooled data, at Day 8, with LOCF, the rates of pain-free patients were statistically significantly larger with Durezol QID (58%) as compared to placebo (27%), for a difference in rates of 31%. At Day 15, 63% of the patients treated with Durezol were pain/discomfort free compared to 35% of the patients that received placebo. The difference in rates was 28% with LOCF. The benefit of Durezol started as early as Day 3 (20%).

Using the same dataset with LOCF, the proportion of patients with an AC Cell Count = 0 and pain-free was statistically significantly larger with Durezol (15% on Day 8, 32% on Day 15) as compared to the placebo (6% on Day 8, 7% on Day 15), with a difference in rates of 9.5% on Day 8, and 25% on Day 15.

Overall, the efficacy data of both pivotal studies (Studies 002a and 002b) provided acceptable evidence to support the efficacy of Durezol for the treatment of ocular inflammation following cataract surgery. The proposed indication with the wording "for the treatment of inflammation and pain associated with ocular surgery" was revised to the more restricted "for the treatment of inflammation and pain associated with post-operative inflammation following cataract surgery" to more accurately reflect the two pivotal clinical studies.

Endogenous anterior uveitis

The two pivotal studies (Studies C-10-034 and 001) were randomized, double-blind, active-controlled, Phase III non-inferiority studies. A total of 200 patients with endogenous anterior uveitis were randomized to receive Durezol or prednisolone ophthalmic solution 1%. A total of 106 patients received Durezol QID. The PP population used in the efficacy analysis (no-inferiority) consisted of 180 patients (Durezol 94 and prednisolone 86). Patients with mild to moderate endogenous anterior uveitis received Durezol 0.05% QID or prednisolone 8 times daily for 14 days. After Day 14, the medications were gradually reduced during 14 days. After the tapering period (up to Day 28), an additional time period of 14 days followed during which the treatment was at the physician's discretion.

The primary efficacy endpoint for both studies was the change from baseline in AC cell grade on Day 14 between Durezol 0.05% ophthalmic emulsion and prednisolone ophthalmic suspension 1%. Anterior chamber cell grade was determined using a 5 unit scale ranging from 0 (≤1 cell) to 4 (>50 cells). The non-inferiority margin used was 0.5 units, meaning that the upper limit of the two-tailed 95% confidence interval (CI) must have been less than 0.5 to establish non-inferiority.

In both studies, Durezol was found to be non-inferior to prednisolone at Day 14. This conclusion was drawn from analysis in Study C-10-034 and Study 001 that showed that the upper 95% CI on the difference in mean change from baseline was less than 0.5 units. Durezol 0.05% QID was found to be non-inferior to prednisolone ophthalmic suspension 1% 8 times daily, with a mean AC cell grade reduction of 2.2 in the Durezol group and 2.0 in the prednisolone group (upper 95% CI of the differences between the means was 0.09) in Study C-10-034, and a mean AC cell grade reduction of 2.1 in the Durezol group and 1.9 in the prednisolone group [upper 95% confidence level (CL) 0.22) in Study 001. These findings represent an approximate 2-grade improvement from baseline at Day 14 in both treatment groups. The results in the PP population for this measure were supported by nearly identical results in the ITT population in both studies. Both populations used the LOCF method for imputing missing data.

Some of the secondary efficacy findings are listed below:

• The proportion of patients with AC cell clearing (count = 0) tended to be somewhat greater in the Durezol group as compared to the prednisolone group in many of the time points, however, the results did not reach statistical significance.
• The mean change from baseline in AC flare grade in Studies C-10-034 and 001 at all time points appeared not significantly different between the treatment groups.

Overall, the efficacy data of both pivotal studies (Studies C-10-034 and 001) provided acceptable evidence to support the efficacy of Durezol for the treatment of endogenous anterior uveitis.

For more information, refer to the Durezol Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Overall, a total of 541 patients were exposed to Durezol in 5 uveitis studies (two of which were pivotal: Studies C-10-034, and 001, and 6 post-cataract surgery studies (two of which were pivotal: Studies 002a and 002b). Of these patients, 39 patients participated in a pediatric study (Study C-10-004) of inflammation following cataract surgery. The patients received Durezol QID for at least 14 days followed by a tapering regimen (halving of the number of doses per day at each step based on medical judgment). The pivotal studies are also described in the Clinical Efficacy section.

In the two pivotal uveitis studies, patients with mild to moderate endogenous anterior uveitis received Durezol 0.05% QID or prednisolone 8 times daily for 14 days. Pooling the two studies showed that most adverse events (AEs) were eye-related events and occurred more frequently in the study eye of patients treated with Durezol vs. prednisolone (46% vs. 39%). Durezol elicited more eye disorders than prednisolone (41.5% vs. 35%). The very common AEs (≥10%) were punctate keratitis and increased intraocular pressure (IOP). Common AEs (1% to <10%) were eye irritation, anterior chamber flare, dry eye, corneal edema, and blindness transient. Durezol's common AEs with frequencies similar to prednisolone were iridocyclitis, conjunctival hyperaemia, limbal hyperaemia, uveitis, visual acuity reduced, anterior chamber inflammation, iritis, and photophobia. Serious adverse events (SAEs) were found in 3 (2.8%) patients in the pivotal studies: necrotizing retinitis, hypertension, and chest pain (non-cardiac). In the supplemental uveitis studies, SAEs were reported in 2 (2.1%) patients: necrotizing retinitis and monoarthritis. None of the events was considered related to the study drug by the investigators. Withdrawal from study drug due to AEs was reported for 2 (1.0%) of the patients in the Durezol group compared with 6 (6.4%) subjects in the prednisolone group. The events in Durezol were necrotizing retinitis and sinusitis, asthenia, malaise, and nausea considered not serious.

In the two pivotal post-cataract surgery studies, patients with ocular inflammation following cataract surgery were randomized to receive Durezol or placebo. When the results of the two pivotal studies were pooled together, ocular AES were reported in 51.4% of patients that received Durezol QID compared to 80.9% of patients that received placebo. The most frequently reported ocular adverse reactions reported with Durezol QID included corneal and conjunctival edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber cells, anterior chamber flare, and blepharitis.

Increases in IOP were clearly related to Durezol. An IOP increase as an AE (which correspond to large clinically significant increases of ≥10 mmHg) was reported in 2 to 3% of patients treated with Durezol and 1% of those with placebo. An IOP increase of ≥8 mm Hg was reported in 13% of patients with Durezol and 4% of those with placebo.

Serious AEs were reported in 5 (2.3%) patients with Durezol and 2 patients (0.9%) with placebo; however, none of these events were ocular (headache, pneumonia, urinary tract infection, dehydration, atrial fibrillation) or considered related to the study drug (no discontinuation was required). No significant finding for lens opacification was noted, probably due to relatively short duration of treatment. No issue were reported by the sponsor regarding changes in visual acuity, fundus parameters, ocular infection status, and other ocular signs.

In a separate clinical study (C-10-004), Durezol was studied in 39 children aged 28 days to 3 years with inflammation following cataract surgery. The control patients were treated with prednisolone acetate ophthalmic suspension 1.0%. Adverse drug reactions included severe increased IOP (two patients, one of which was serious) and corneal edema (one patient). No significant safety issues were reported in the small pediatric study. The safety profile of Durezol administered QID for 14 days and tapered thereafter was found acceptable in these children.

Other clinical studies provided information that were of lesser quality or value but overall, were in line with that of the pivotal studies. In the supportive studies, the most frequently reported AEs were increased IOP and punctate keratitis. Plasma cortisol levels obtained from 201 patients in various studies did not raise any significant concern (only 1 elevated cortisol was considered related to Durezol). No drug-demographics interaction analyses were performed, but the safety and AE data collected to date do not show any safety issues in clinical subpopulations, or in concomitant use of usual post-surgery medications (for example, antibiotics).

A total of 4.1 million units of Durezol have been sold or distributed in the United States since 2008. During this 4-year post-marketing experience, there was no individual event that would be indicative of an overall product problem, and no issues or trends were identified that would represent a previously unknown concern.

Overall, the safety profile of Durezol in the study population was in line with the expected profile of topical ocular corticosteroids. Appropriate warnings and precautions are in place in the approved Durezol Product Monograph to address the identified safety concerns.

For more information, refer to the Durezol Product Monograph, approved by Health Canada and available through the Drug Product Database.