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Mechanism of Action
Corticosteroids inhibit the inflammatory response to a variety of inciting agents and may delay or slow healing. They inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.
Difluprednate is structurally similar to other corticosteroids.
Difluprednate undergoes deacetylation in vivo to 6α,9-difluoroprednisolone 17-butyrate (DFB), an active metabolite of difluprednate.
Clinical pharmacokinetic studies of difluprednate after repeat ocular instillation of 2 drops of difluprednate (0.01% or 0.05%) four times per day 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.
Animal Toxicology and/or Pharmacology
In multiple studies performed in rodents and non-rodents, subchronic and chronic toxicity tests of difluprednate showed systemic effects such as suppression of body weight gain; a decrease in lymphocyte count; atrophy of the lymphatic glands and adrenal gland; and for local effects, thinning of the skin; all of which were due to the pharmacologic action of the molecule and are well known glucocorticosteroid effects. Most, if not all of these effects were reversible after drug withdrawal. The NOEL for the subchronic and chronic toxicity tests were consistent between species and ranged from 1–1.25 mcg/kg/day.
Clinical efficacy was evaluated in 2 randomized, double-masked, placebo-controlled trials in which subjects with an anterior chamber cell grade ≥ “2” (a cell count of 11 or higher) after cataract surgery were assigned to DUREZOL or placebo (vehicle) following surgery. One drop of DUREZOL or vehicle was self instilled either 2 times per day or 4 times per day for 14 days, beginning the day after surgery. The presence of complete clearing (a cell count of 0) was assessed 8 and 15 days post-surgery using a slit lamp binocular microscope. In the intent-to-treat analyses of both studies, a significant benefit was seen in the 4 times per day DUREZOL –treated group in ocular inflammation and reduction of pain when compared with placebo. The consolidated clinical trial results are provided below.
Ocular Inflammation and Pain Endpoints (Studies
|Day||DUREZOL 4 times per day
|Anterior Chamber cell clearing (% subjects)||24 (22%)*||44 (41%)*||17 (7%)||25 (11%)|
|Pain free (% subjects)||62 (58%)*||67 (63%)*||59 (27%)||76 (35%)|
|* Statistically significantly better than vehicle, P < 0.01|
Endogenous Anterior Uveitis
Clinical efficacy was evaluated in two randomized, double masked active controlled trials in which patients who presented with endogenous anterior uveitis were treated with either DUREZOL 4 times daily or prednisolone acetate ophthalmic suspension, 1%, 8 times daily for 14 days. Both studies demonstrated that DUREZOL was equally effective as prednisolone acetate ophthalmic suspension, 1% in treating subjects with endogenous anterior uveitis.
Mean Change from Baseline in Anterior Chamber Cell
|Study 1 time point||DUREZOL
|Baseline||2.6||2.5||0.0 (-0.22, 0.28)|
|Day 3||-1.0||-1.0||-0.1 (-0.35, 0.25)|
|Day 7||-1.6||-1.5||-0.0 (-0.31, 0.25)|
|Day 14||-2.0||-1.8||-0.2 (-0.46, 0.10)|
|Day 21||-2.2||-1.9||-0.3 (-0.53, 0.01)|
|Day 28||-2.2||-2.1||-0.1 (-0.37, 0.18)|
|Day 35||-2.1||-2.0||-0.1 (-0.39, 0.20)|
|Day 42||-2.1||-2.1||0.0 (-0.27, 0.34)|
|Study 2 time point||DUREZOL N=50||Prednisolone Acetate
|Baseline||2.4||2.4||0.0 (-0.21, 0.29)|
|Day 3||-0.9||-0.9||-0.0 (-0.34, 0.25)|
|Day 7||-1.7||-1.6||-0.1 (-0.35, 0.21)|
|Day 14||-1.9||-1.8||-0.1 (-0.34, 0.20)|
|Day 21||-2.0||-2.0||0.0 (-0.25, 0.28)|
|Day 28||-2.0||-2.0||0.0 (-0.21, 0.26)|
|Day 35||-2.1||-2.0||-0.1 (-0.32, 0.16)|
|Day 42||-2.0||-1.9||-0.1 (-0.36, 0.24)|
|* with 5 grades: 0 = 0 cells; 1 = 1 to 10 cells; 2 = 11
to 20 cells; 3 = 21 to 50 cells; and 4 = > 50 cells.
** adjusted for baseline AC cell grade and study center and based on ITT dataset with LOCF for missing data.
Last reviewed on RxList: 4/4/2013
This monograph has been modified to include the generic and brand name in many instances.
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