Higher-concentration drug statistically superior to vehicle for achieving resolution of inflammation
A new 0.3% formulation of nepafenac ophthalmic suspension (Ilevro, Alcon Laboratories) is approved for once-daily dosing in the treatment of pain and inflammation associated with cataract surgery.
By Cheryl Guttman Krader; Reviewed by Edward Holland, MD
Cincinnati-Nepafenac 0.3% ophthalmic suspension (Ilevro, Alcon Laboratories) is an important advance for the management of pain and inflammation associated with cataract surgery.
The new product delivers the efficacy and safety surgeons have come to expect when prescribing its predecessor, nepafenac 0.1% (Nevanac, Alcon), with the added benefit of once-daily (QD) dosing, according to Edward Holland, MD.
The unique formulation of nepafenac with enhanced pharmacokinetics properties enables reduced-dosing frequency. In addition to containing a three-fold higher concentration of active ingredient, the particle size of nepafenac in the new product is smaller (~40%) relative to that found in nepafenac 0.1%. The result is faster dissolution of the prodrug in the new 0.3% preparation and attainment of an approximately two-fold higher aqueous humor concentration (maximum and area-under-the curve) after a single dose.
In addition, guar gum, propylene glycol, and carboxymethylcellulose have been added as an excipient in the new product, which together with the reduced total drop burden makes the formulation ocular surface friendly, said Dr. Holland, director of cornea, Cincinnati Eye Institute, and professor of ophthalmology, University of Cincinnati, Cincinnati, OH.
“Nepafenac 0.3% should increase compliance with its convenient QD dosing, and as demonstrated in clinical trials, provides that opportunity without compromising efficacy and safety,” he said.
FDA approval of nepafenac 0.3% for the treatment of inflammation and pain associated with cataract surgery was based on the safety and efficacy data from two multicenter, randomized, double-masked pivotal trials-one that established the superiority of the new product for eliminating inflammation and pain compared with vehicle and the other showing its non-inferiority versus nepafenac 0.1% three-times daily (TID). The vehicle-controlled study included more than 800 patients, and the active comparator trial enrolled more than 2,000 patients, making it the largest ever active comparator-controlled trial of an ophthalmic NSAID, Dr. Holland noted.
In the vehicle-controlled study, patients were randomly assigned 2:1 to nepafenac 0.3% or vehicle QD. The active comparator trial randomly assigned patients 4:1:4:1 to nepafenac 0.3% QD, nepafenac 0.3% vehicle QD, nepafenac 0.1% TID, or nepafenac 0.1% vehicle TID. In both studies, all treatments were started the day before surgery and continued for 14 days after surgery. On the day of surgery, patients receiving nepafenac 0.3% or its vehicle were administered an extra drop 30 to 120 minutes prior to surgery.
Complete clearing of inflammation (0 cells and 0 flare) at day 14 postoperatively was analyzed as the primary efficacy variable in both studies. This endpoint was achieved by 61% and 65% of nepafenac 0.3% patients in the vehicle- and active-controlled studies, respectively, 67% of patients treated with nepafenac 0.1% TID, and 24% to 34% of patients in the various vehicle groups. Rates for proportion of patients who were pain-free at day 14 were 84% and 86% for the nepafenac 0.3% groups in the two trials, 87% for patients treated with nepafenac 0.1% TID, and 38% to 54% for the vehicle groups.
“Nepafenac 0.3% was also statistically superior to its vehicle for achieving resolution of inflammation by day 7, and its treatment effect over vehicle for pain resolution occurred as early as day 1,” Dr. Holland said.
Across the two trials, more than 1,300 patients were treated with nepafenac 0.3%. No new safety concerns emerged with the higher-concentration nepafenac product, and in the active comparator trial, the two nepafenac formulations had similar safety profiles. Tolerability was good, and there were no reports of visual blur, despite the increased viscosity of the 0.3% preparation, Dr. Holland said.
“The guar gum in the new formulation of nepafenac not only acts as a viscosity enhancer to increase ocular surface retention, but along with propylene glycol and carboxymethylcellulose, this new formulation is very good for the ocular surface,” he added.
“Furthermore, total drop burden with the recommended 16 days of use is decreased from 48 drops using nepafenac 0.1% to just 17 drops with the 0.3% formulation,” Dr. Holland said. “The result is reduced ocular surface exposure to NSAID and benzalkonium chloride, which can only be a good thing for the corneal epithelium.”
Edward Holland, MD
Dr. Holland is a consultant to Alcon Laboratories, Allergan, and Bausch + Lomb.