Nevanac (Nepafenac Ophthalmic) - Description and Clinical Pharmacology

DESCRIPTION

NEVANAC^® (nepafenac ophthalmic suspension) 0.1% is a sterile, topical, nonsteroidal anti-inflammatory (NSAID) prodrug for ophthalmic use. Each mL of NEVANAC^® suspension contains 1 mg of nepafenac. Nepafenac is designated chemically as 2-amino-3-benzoylbenzeneacetamide with an empirical formula of C₁₅H₁₄N₂O₂. The structural formula of nepafenac is:

Nepafenac is a yellow crystalline powder. The molecular weight of nepafenac is 254.28. NEVANAC^® ophthalmic suspension is supplied as a sterile, aqueous 0.1% suspension with a pH approximately of 7.4.

The osmolality of NEVANAC^® ophthalmic suspension is approximately 305 mOsmol/kg.

Each mL of NEVANAC^® contains: Active: nepafenac 0.1% Inactives: mannitol, carbomer 974P, sodium chloride, tyloxapol, edetate disodium, benzalkonium chloride 0.005% (preservative), sodium hydroxide and/or hydrochloric acid to adjust pH and purified water, USP.

CLINICAL PHARMACOLOGY

Mechanism of Action

Nepafenac (0.1%) is a nonsteroidal anti-inflammatory and analgesic prodrug. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a nonsteroidal anti-inflammatory drug. Amfenac is thought to inhibit the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.

Pharmacokinetics

Gender: Data in healthy subjects indicate no clinically relevant or significant gender difference in the steady-state pharmacokinetics of amfenac following three-times-daily dosing of NEVANAC^®.

Low but quantifiable plasma concentrations of nepafenac and amfenac were observed in the majority of subjects 2 and 3 hours postdose, respectively, following bilateral topical ocular three-times-daily dosing of nepafenac ophthalmic suspension, 0.1%. The mean steady-state Cmax for nepafenac and for amfenac were 0.310 ± 0.104 ng/ml and 0.422 ± 0.121 ng/ml, respectively, following ocular administration.

NONCLINICAL TOXICOLOGY SECTION

Carcinogenesis and Mutagenesis and Impairment of Fertility

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 5,000 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 (approximately 90 and 380 times the plasma exposure to the parent drug, nepafenac, and the active metabolite, amfenac, respectively, at the recommended human topical ophthalmic dose).

CLINICAL STUDIES

In two double-masked, randomized clinical trials in which patients were dosed three-times-daily beginning one day prior to cataract surgery, continued on the day of surgery and for the first two weeks of the postoperative period, NEVANAC^® ophthalmic suspension demonstrated clinical efficacy, compared to its vehicle in treating postoperative inflammation.

Patients treated with NEVANAC^® ophthalmic suspension were less likely to have ocular pain and measurable signs of inflammation (cells and flare) in the early postoperative period through the end of treatment than those treated with its vehicle.

For ocular pain in both studies a significantly higher percentage of patients (approximately 80%) in the nepafenac group reported no ocular pain on the day following cataract surgery (Day 1) compared to those in the vehicle group (approximately 50%).

Results from clinical studies indicated that NEVANAC^® has no significant effect upon intraocular pressure; however, changes in intraocular pressure may occur following cataract surgery.