Rx Perspective

Taking Aim at Post-Surgical Inflammation

A new topical steroid could improve outcomes by simplifying the postop regimen.

By Robert J. DaVanzo, M.D.

Inflammation is common after cataract and other ocular surgeries, manifesting as pain, redness and discomfort. If left untreated, it can interfere with a patient's visual rehabilitation or lead to further complications, most notably cystoid macular edema (CME). The incidence of acute, visually significant CME has been reported to be from 1% to 2% of patients following uncomplicated phacoemulsification.^1,2

CME may also develop over the longer term, from 6 weeks to 3 months after surgery. Studies using optical coherence tomography have suggested CME may be under-diagnosed, with as many as 20% to 30% of postoperative patients developing it even in the absence of symptoms.^3-5

For both patient comfort and safety, it's important to reduce inflammation quickly to reduce risk of complications and to give the patient the best possible vision in the shortest period of time. A combination of an NSAID and steroid is typically prescribed after surgery.

How it Works

Difluprednate 0.05%, a topical corticosteroid, was recently approved by the FDA to treat postoperative inflammation and pain associated with ocular surgery. Marketed as Durezol by Sirion Therapeutics of Tampa, Fla, it is a difluorinated derivative of prednisolone in an emulsion formulation. Its anti-inflammatory activity results from molecular engineering of side chains to make the steroid stronger, improve its ability to enter the eye at a high concentration, maximize its affinity for steroid receptors and ensure that it becomes inactivated relatively quickly after performing its anti-inflammatory actions.

The Durezol approval was announced after a 6-month priority review by the FDA based on two identical phase 3 clinical trials in which I participated, each of which assessed the drug dosed either two times or four times daily vs. placebo beginning 24 hours after intraocular surgery, largely cataract procedures. The studies included 438 subjects who presented with significant inflammation, as evidenced by an anterior chamber cell grade of 2 or higher (defined as greater than 10 cells) the day after surgery. Treatment was tapered over 4 weeks.⁶

Clinical Results

Patients treated with Durezol showed statistically significant differences from placebo from the first postoperative visit by day 3 or 4. The difference from placebo increased with time in both the b.i.d. and q.i.d. arms of the study for both the primary endpoint (anterior chamber cell grade of 0, one or no cells) and for pain.

At 2 weeks postoperatively, the number of cells in the anterior chamber for both the b.i.d. and q.i.d. arms was reduced by 87%. The q.i.d. regimen demonstrated a small numerical advantage in the amount of patients who were completely free of inflammation and pain at the 1-week postop time point.⁷

Given the disappointing performance of other topical steroids in recent years, it would not surprise me to encounter skepticism about yet another new option. However, Durezol is the first steroid medication whose ability to control pain has been demonstrated and which has received an indication specifically for pain as well as inflammation. In my experience, Durezol seems to be more efficacious than other steroid drops. The clinical data from the phase 3 trials, based on actual counts of the inflammatory cells, showed it is effective at b.i.d. dosing, among patients who already had a significant level of inflammation (grade 2 or higher).

In Japan, several studies have shown that Durezol is effective in treating severe cases of inflammatory uveitis at QID dosing, including panuveitis.^8,9 A study is currently underway that compares Durezol dosed QID with Pred Forte dosed eight times daily for anterior uveitis, and I am eager to see how Durezol on a less frequent dosing schedule compares to the standard of care. Achieving comparable efficacy with a simpler regimen would be a significant improvement for patients and physicians.

Unlike other strong ophthalmic steroids, Durezol has only a minimal effect on IOP rise. Only 3% of patients in the b.i.d. and q.i.d. groups experienced a clinically significant rise — defined as an observed value of greater than or equal to 21mm Hg and a change from baseline of 10mm Hg — compared with 1% in the placebo group.

It was noteworthy that not one patient in the three Durezol studies I have worked on experienced a significant rise in IOP, nor did I notice complaints of discomfort such as burning or stinging. Durezol is preserved with sorbic acid rather than BAK, and thus is less irritating to the eye.

Practice Implications

A postoperative steroid that can be effective at a b.i.d. regimen could improve compliance and simplify follow-up visits. We know that b.i.d. dosing schedules improve compliance, which is even more of an issue for elderly patients who are often already on a variety of medications.

Durezol's emulsion formulation enhances penetration but also has the advantage of obviating the need for shaking the bottle prior to administration. Shaking is an issue for some elderly patients in my practice, as some do not have the physical coordination and inadequate shaking may not deliver the right amount of medication. In addition, sediment in suspension-based ophthalmic medications may cause crusting on the eye.

Figure 1 above shows the results for one postoperative patient in the phase 3 study, an 87-year-old woman whose compromised ocular surface and history of herpes zoster increased her risk of serious post-operative inflammation. She received Durezol b.i.d. starting 1 day after cataract surgery, when her inflammation was grade 3. By day 4, the inflammation was reduced to grade 1 and at day 8 to 0. At day 15, her regimen was tapered to once-daily (QD) and at day 36 — 1 week after discontinuation of therapy — her cell grade remained at 0.

Durezol should be commercially available later this year, according to the manufacturer. I am excited by the prospect of a steroid that is strong enough to reduce postoperative inflammation quickly, on a convenient dosing schedule, but without a significant rise in IOP. We simply have not seen this combination of strength and tolerability with other ophthalmic steroids. OM

References

1. Ray S, D'Amico DJ. Pseudophakic cystoid macular edema. Semin Ophthalmol. 2002;17(3-4):167-180.
2. Henderson BA, Kim JY, Ament CS, et al. Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment. J Cataract Refract Surg. 2007;33(9):1550-1558.
3. Solomon LD. Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group I. J Cataract Refract Surg. 1995;21(1):73-81.
4. Ursell PG, Spalton DJ, Whitcup SM, Nussenblatt RB. Cystoid macular edema after phacoemulsification: relationship to blood-aqueous barrier damage and visual acuity. J Cataract Refract Surg. 1999;25(11): 1492-1497.
5. Flach AJ. The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery. Trans Am Ophthalmol Soc. 1998;96:557-634.
6. Korenfeld, M. Difluprednate Ophthalmic Emulsion, 0.05%, Phase 3 Efficacy Results in the Treatment of Inflammation Following Ocular Surgery. ASCRS 2008.
7. Korenfeld M. Difluprednate Ophthalmic Emulsion, 0.05%, Phase 3 Efficacy Results in the Treatment of Inflammation Following Ocular Surgery. ASCRS 2008.
8. Ohno S. et al. A Phase III, Non-inferiority Study of Difluprednate Ophthalmic Emulsion (DFBA), 0.05%, in the Treatment of Anterior Uveitis. ARVO 2007.
9. Mochizuki M. et al. A Phase III, Open Label, Clinical Study of Difluprednate Ophthalmic Emulsion (DFBA), 0.05%, in the Treatment of Severe Refractory Anterior Uveitis. ARVO 2007.