Rx Perspectives

Acuvail: Simpler Dosing, Improved Comfort

By Eric D. Donnenfeld, MD

Topical NSAID use before and after cataract surgery has resulted in an enormous improvement in visual outcomes. But because QID dosing and patient discomfort upon instillation can lead to noncompliance, simpler regimens and gentler formulations have been the focus of drug development in recent years.

Improvements on both fronts are highlights of the newly-approved Acuvail (ketorolac 0.45%) from Allergan, the first twice-daily non-preserved, unit-dose topical NSAID. The drug has been formulated for better performance, comfort, penetration and bioavailability. Surgeons who add it to their cataract regimen can expect both greater efficacy and compliance.

The new drug enhances ketorolac bioavailability because its pH of 6.8 enables deionized drug delivery and improves drug penetration into the eye. In fact, the peak and trough anterior chamber levels of ketorolac are higher with Acuvail BID than Acular LS QID. Another unique feature is its use of carboxymethylcellulose as a vehicle, which promotes adherence of the active agent to the ocular surface while also improving bioavailability and comfort. Other topical NSAIDs use an aqueous vehicle.

The FDA trial found Acuvail better tolerated, with significantly fewer adverse events than the control. Its burning and stinging incidence was only 1.5% (5/330).¹ The results were impressive enough to allow labeling for the elimination of pain and inflammation following cataract surgery; older topical NSAIDs are labeled for reduction of pain and inflammation. In fact, the FDA trial showed a two-to-one elimination of inflammation compared to control.

FDA Trial Data
The efficacy and safety of ketorolac 0.45% were investigated in two multi-center, double-masked prospective trials enrolling more than 500 patients. Subjects were randomized 2:1 to twice-daily treatment with ketorolac 0.45% or vehicle control for 16 days.¹ All patients were instructed to begin administering their assigned agent on the day before surgery.

Resolution of inflammation at postop day 14, the primary efficacy endpoint, showed the statistically significantly superior efficacy of ketorolac 0.45% versus the vehicle. Fifty-two percent of ketorolac patients and only 26% of controls achieved a summed ocular inflammation score of zero cell and flare (P<0.001). The efficacy of ketorolac 0.45% BID was actually documented much earlier. By postoperative day seven, 32% of ketorolac-treated patients had already achieved complete elimination of inflammation, as evidenced by no cells in the anterior chamber, compared with only 17% of controls. The benefit of ketorolac was statistically significant and clinically impressive.

Pain relief was a secondary outcome measure, and the FDA data showed that ketorolac was also highly effective in controlling pain. On the first day after surgery, nearly three-quarters of ketorolac patients (72%) were completely free of pain compared with only 40% of patients in the control group (P<0.001).

Visual recovery following cataract surgery is especially important to patients. In the study, 60.5% of ketorolac patients gained three or more lines of best-corrected visual acuity at day 14 versus 44.0% for controls (P=0.002).

NSAIDs reduce pain and inflammation by inhibiting the production of prostaglandins by cyclooxygenase (COX), which has two isoforms: COX-1, the constitutive enzyme, and COX-2, the inducible form. The results of previous studies indicate that inhibiting both of these isoforms is important for preventing prostaglandin release after the trauma induced by ocular surgery^2,3 The efficacy of Acuvail can be attributed to its intrinsic broad-spectrum properties as a potent inhibitor of both COX-1 and COX-2, along with the enhanced bioavailability characteristics of this new formulation of ketorolac.

Acuvail is a very different product than the previous formulation, and achieves therapeutic levels that could not be accomplished with the older version. The drug is expected to be available to patients and physicians later this month. With its potent antiinflammatory effect and patient-friendly twice-a-day dosing, I believe Acuvail is a welcome addition to the cataract surgery armamentarium. OM

References

1. Donnenfeld ED, Nichamin LD, Hardten HR, et al. Efficacy and tolerability of twice-daily, preservative-free ketorolac 0.45% for treatment of postcataract surgery pain and inflammation. FDA trial.
2. Solomon KD, Donnenfeld ED, Raizman M, et al. Ketorolac Reformulation Study Groups 1 and 2. Safety and efficacy of ketorolac tromethamine 0.4% ophthalmic solution in post-photorefractive keratectomy patients. J Cataract Refract Surg. 2004;30:1653-1660.
3. Perry HD, Donnenfeld ED. An update on the use of ophthalmic ketorolac tromethamine 0.4%. Expert Opin Pharmacother. 2006;7(1):99-107.

Eric D. Donnenfeld, MD, is a trustee of Dartmouth Medical School in Hanover NH, and a partner in Ophthalmic Consultants of Long Island in Rockville Centre, NY. He is a consultant to Allergan, Inc. He may be reached at (516) 766-2519 or eddoph@aol.com.