February 2010

 

CATARACT / IOL

 

New ketorolac to improve compliance, efficacy


by Michelle Dalton EyeWorld Contributing Editor

   

Acuvail has a lower pH than Acular and less frequent dosing

A new formulation of ketorolac has been developed to “improve the efficacy of prior formulations while enhancing tolerability, coupled with a less frequent dosing regimen,” said Eric D. Donnenfeld, M.D., co-chairman, Cornea, Nassau University Medical Center, East Meadow, N.Y. Dr. Donnenfeld presented on the new formulation during the 2009 European Society of Cataract and Refractive Surgeons meeting in Barcelona, Spain. The new drug, Acuvail (ketorolac 0.45%, Allergan, Irvine, Calif.) has “four noted changes from the Acular versions,” Dr. Donnenfeld said. Acular LS is ketorolac 0.4%, while Acular is ketorolac 0.5%. “Changing from 0.4% to 0.45% is not a big difference,” he said. Likewise, the unit dosing is different between Acular and Acuvail. The third difference, however, “is that Acuvail has a pH of 6.8, and that changes it dramatically from earlier versions and makes it much more effective,” Dr. Donnenfeld said. Both earlier versions of ketorolac have a pH of 7.4, Dr. Donnenfeld explained, which is where the molecule falls naturally. “If the pH had been left where it was before, it would not have been as bioavailable. Forcing the molecule to a lower pH allows it to become effective and also allows for twice-daily dosing.”

The fourth change is the addition of carboxymethylcellulose, which acts as a sustained release vehicle for higher tissue levels, dramatically increased comfort, and protection of the ocular surface. Rabbit studies on the newer formulation found the combination of carboxymethylcellulose and the lower pH resulted in a 2- to 3-fold higher bioavailability to ocular tissues, he said.

Clinical trial results

Two randomized, controlled clinical studies* compared the efficacy and safety of twice-daily ketorolac 0.45% for the treatment of inflammation and pain following cataract surgery. The first study included 318 patients in the ketorolac 0.45% group and 155 patients in the vehicle group; the second study had 322 patients in the ketorolac 0.45% group and 156 in the vehicle group. In both studies, the primary eligibility criterion was uncomplicated, extracapsular phacoemulsification with posterior chamber IOL implantation. Both groups received twice-daily dosing of the drug/vehicle beginning the day before surgery and continuing 14 days post-surgery. Study endpoints included the percentage of patients with summed ocular inflammation score (SOIS) of 0 for anterior chamber cell and flare on day 14. Endpoints were evaluated on post-op days 1, 3, 7, and 14. Almost twice as many subjects in the ketorolac group had an SOIS score of 0 when compared to those in the vehicle group (52.5% vs. 26.5% at day 14). Likewise, 72.4% of subjects in the ketorolac 0.45% group had a pain score of 0 on day 1 compared with 39.7% of those in the vehicle group. Further, significantly more subjects treated with ketorolac 0.45% had at least 3 lines of improvement in best-corrected visual acuity from baseline (60.5% vs. 44% at day 14; P=.002).

As for adverse events, one subject (0.6%) in the vehicle group and five subjects (1.5%) in the ketorolac group reported burning/stinging upon instillation. “Acuvail has a much higher penetration of the anterior chamber than Acular LS,” Dr. Donnenfeld said. “Acuvail is dosed twice daily and Acular LS is dosed four times a day.”

In his opinion, most patients have a difficult time adhering to the four times-daily dosing. “I think eventually all of our perioperative medications will move to twice-daily dosing,” Dr. Donnenfeld said.

Not a replacement

According to Dr. Donnenfeld, Acuvail also provides broad spectrum inhibition of the COX-1 and COX-2 enzymes. Inhibition of both enzymes is required to inhibit the development of prostaglandins, which are considered to be the primary sources of pain and inflammation after cataract surgery.

The earlier versions of ketorolac will still be available, “just like previous generations of fluoroquinolones are still around,” Dr. Donnenfeld said. In his opinion, however, “when I’m thinking about improving patient outcomes, I don’t want to use an older generation of ketorolac because I don’t want to compromise with my patients’ vision.”

The clinical study results are impressive, Dr. Donnenfeld said. “The results here are so good [the Food and Drug Administration] has approved Acuvail not for the reduction of cell and flare like previous generation non-steroidal anti-inflammatory drugs, but for the elimination of cell and flare,” he said. Acuvail was approved by the Food and Drug Administration in July 2009; shipments began in September.

Editors’ note: Dr. Donnenfeld has financial interests with Allergan (Irvine, Calif.).

* Co-investigators for the two studies include Dr. Donnenfeld; Louis D. Nichamin, M.D., David R. Hardten, M.D., Michael B. Raizman, M.D., William B. Trattler, M.D., Rajesh K. Rajpal, M.D., Louis M. Alpern, M.D.; and Carlos Felix, M.S., Ronald R. Bradford, R.Ph., Linda Villanueva, C.O.T., David A. Hollander, M.D., and Rhett M. Schiffman, M.D., M.S., M.H.S.A.

Contact information

Donnenfeld: 516-446-3525, eddolph@aol.com

New ketorolac to improve compliance, efficacy New ketorolac to improve compliance, efficacy
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