Source: FDA, National Drug Code (US) Revision Year: 2020
After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a NSAID. Nepafenac and amfenac are thought to inhibit the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.
Following bilateral topical ocular once-daily dosing of ILEVRO 0.3%, the concentrations of nepafenac and amfenac peaked at a median time of 0.5 hour and 0.75 hour, respectively on both Day 1 and Day 4. The mean steady-state Cmax for nepafenac and for amfenac were 0.847 ± 0.269 ng/mL and 1.13 ± 0.491 ng/mL, respectively.
Nepafenac at concentrations up to 3000 ng/mL and amfenac at concentrations up to 1000 ng/mL did not inhibit the in vitro metabolism of six specific marker substrates of cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Therefore, drug-drug interactions involving CYP mediated metabolism of concomitantly administered drugs are unlikely.
Nepafenac has not been evaluated in long-term carcinogenicity studies. Increased chromosomal aberrations were observed in Chinese hamster ovary cells exposed in vitro to nepafenac suspension. Nepafenac was not mutagenic in the Ames assay or in the mouse lymphoma forward mutation assay. Oral doses up to 5000 mg/kg did not result in an increase in the formation of micronucleated polychromatic erythrocytes in vivo in the mouse micronucleus assay in the bone marrow of mice.
Nepafenac did not impair fertility when administered orally to male and female rats at 3 mg/kg.
In two double masked, randomized clinical trials in which patients were dosed daily beginning one day prior to cataract surgery, continued on the day of surgery and for the first two weeks of the postoperative period, ILEVRO 0.3% demonstrated superior clinical efficacy compared to its vehicle in treating postoperative pain and inflammation.
Treatment effect over vehicle for resolution of ocular pain occurred as early as Day 1 postsurgery. Treatment effect over vehicle for resolution of inflammation was significantly better than vehicle in both studies at Day 7 and Day 14 post-surgery.
Table 1. Inflammation and Ocular Pain Resolution Results of Nepafenac Ophthalmic Suspension, 0.3% versus Vehicle at Day 14 Postsurgery (All-Randomized Population):
| Study | Treatment | Inflammation Resolution at Postop Day 14 | Ocular Pain Resolution at Postop Day 14 |
|---|---|---|---|
| Study 1 | Nepafenac ophthalmic suspension, 0.3% (n/N)1 | 552/851 (65%) | 734/851 (86%) |
| NEVANAC (n/N)1 | 568/845 (67%) | 737/845 (87%) | |
| Vehicle (n/N)1 | 67/211 (32%) | 98/211 (46%) | |
| Difference (95% CI)2 | 33% (26%, 40%) | 40% (32%, 47%) | |
| Study 2 | Nepafenac ophthalmic suspension, 0.3% (n/N)1 | 331/540 (61%) | 456/540 (84%) |
| Vehicle (n/N)1 | 63/268 (24%) | 101/268 (38%) | |
| Difference (95% CI)2 | 38% (31%, 45%) | 47% (40%, 54%) |
Abbreviation: CI, confidence interval.
1 n/N is the ratio of those with complete resolution of anterior chamber cell and flare by the postoperative Day 14 visit over all randomized subjects.
2 Difference is Nepafenac ophthalmic suspension, 0.3% (n/N) – vehicle. The 95% CI is derived using asymptotic approximation.
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