Farrell “Toby” Tyson, MD, is Medical Director of Cape Coral Eye Center in Cape Coral, Florida. He is a clinical investigator for BROMDAY. Dr. Tyson may be reached at (239) 542-2020; tysonfc@hotmail.com.

The perioperative use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in cataract surgery has become routine due to their ability to control pain and inflammation postoperatively. One of the barriers to patient compliance with NSAIDs, however, is the dosing schedule—typically, these agents are labeled for dosing b.i.d., t.i.d., or q.i.d. following cataract surgery. Fortunately, the leading topical ophthalmic NSAID, bromfenac [XIBROM (bromfenac ophthalmic solution) 0.09%; ISTA Pharmaceuticals, Inc., Irvine, CA], recently gained FDA approval for once-a-day dosing to treat inflammation and pain associated with cataract surgery. BROMDAY (bromfenac ophthalmic solution) 0.09% (ISTA Pharmaceuticals, Inc.) delivers the efficacy ophthalmologists have come to expect from twice daily bromfenac with half the number of drops of XIBROM and a lower medication load than other NSAIDs. I participated as an investigator in the BROMDAY clinical studies; this article summarizes the data from those trials and discusses the potential impact of the first and only q.d. ophthalmic NSAID for cataract surgery on clinical practice.

BROMFENAC EFFICACY
The unique chemical structure of the bromfenac molecule makes it effective as a once daily treatment. Bromfenac is halogenated with bromine, making it very potent against the cyclo-oxygenase (COX) enzymes that are responsible for inflammation and pain.

This halogenation also makes the bromfenac molecule highly lipophilic, enabling it to penetrate the cornea efficiently and maintain high levels of active drug in the anterior chamber.

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Due to its excellent pharmacokinetics and bioavailability, bromfenac successfully controls postoperative inflammation and pain following cataract surgery at a relatively low concentration and with less frequent dosing. The efficacy of bromfenac was underscored in both XIBROM and BROMDAY clinical trials, because it eliminated inflammation without the aid of a topical corticosteroid. In fact, I used XIBROM as a stand-alone anti-inflammatory therapy in cataract surgery for patients not at high risk, and they rarely required rescue with a corticosteroid. I like the idea of eliminating the cost of the steroid for my patients and not having to worry about potential steroid-associated adverse events. Of course, I also expect patient compliance and satisfaction with fewer medications and less frequent dosing.

CLINICAL TRIAL RESULTS
The BROMDAY clinical trials, which involved more than 800 patients, provide robust proof of the efficacy of the drug’s q.d. dosing. Once daily dosing was first investigated in a study comparing two concentrations of bromfenac (data on file, ISTA Pharmaceuticals, Inc.). In three subsequent studies, subjects were pretreated with either BROMDAY or placebo 1 day prior to undergoing cataract surgery, and they were given only BROMDAY or placebo (they did not receive any topical corticosteroids) on the day of surgery and for 14 days postoperatively. Thus, the reduction of inflammation and pain as well as the discontinuation rates in the treatment groups were predicated on 16 drops of BROMDAY alone. The FDA based its approval of BROMDAY on two of the placebo-controlled studies it considered pivotal trials. An integrated analysis of all four studies has also been performed (data on file, ISTA Pharmaceuticals, Inc.).

It is worth noting that all of these studies used complete clearing of inflammation— a summed ocular inflammation score (SOIS) of zero (zero cells and zero flare)—as the primary endpoint. When both the pivotal and integrated results were re-graded to include trace inflammation (0 to 5 cells and zero flare) in the endpoint, mirroring the design of earlier NSAID clinical programs, nearly 8 out of 10 patients treated with BROMDAY achieved success by postoperative day 15. Specifically, 74%to 79% of patients treated with BROMDAY reached zero-to-trace inflammation compared to 40% to 42% of the patients treated with placebo across both the pivotal (two studies) and integrated (four studies) analyses.

Returning to the prospectively-defined primary endpoint, based on the summary of the two pivotal trials provided in the BROMDAY prescribing information, 46% to 47% of BROMDAY-treated patients and 25% to 29% of placebo-treated patients achieved complete clearance of inflammation (SOIS of 0) by day 15. Against the secondary efficacy endpoint, 83% to 89% of patients on BROMDAY and 51% to 71% of patients on placebo reported being pain free at postoperative day 1 in the pivotal trials.

The analysis of the larger integrated data set is consistent with the results of the pivotal trials. Subjects treated with BROMDAY showed a clinically significant reduction of inflammation as early as the eighth postoperative day (after 10 drops of BROMDAY) (Figure 1). At day 15, 51% of patients treated with BROMDAY and 27% of the patients treated with placebo achieved complete clearance of inflammation (SOIS of 0) at postoperative day 15. Additionally, 84% of subjects taking BROMDAY reported feeling no pain on the first postoperative day, compared with 67% of those in the placebo group (Figure 2).

Figure 1. Integrated clinical trial results:mean SOIS at each study visit.

Figure 2. Integrated clinical trial results: proportion of patients reporting no pain at each study day.

Another revealing measure of a medication's success in clinical trials is its discontinuation rate. In the integrated analysis, more than 30% of the subjects in the placebo group had dropped out of the study due to lack of efficacy and had to be rescued with another anti-inflammatory agent (an ophthalmic NSAID and/or ophthalmic corticosteroid) at day 15, compared with less than 3% of the patients in the BROMDAY group.

PATIENT ADHERENCE
Patient adherence to postoperative medical therapy is also affected by the tolerability of the medication. In terms of ocular comfort, the integrated results showed a statistically significant improvement in four out of seven symptoms (pain, tearing, foreign body sensation, and photophobia) in BROMDAY patients compared with those taking the placebo. The incidence of the other three symptoms (itching, eye discharge, and haziness) were comparable to the placebo.

These clinical trial results give me confidence that BROMDAY is as effective as XIBROM with half the dosing.

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