Pharmacotherapeutic group: Anti-inflammatory agents, non-steroids. ATC code: S01BC10.
Pharmacology: Pharmacodynamics: Mechanism of action: Nepafenac is a non-steroidal anti-inflammatory and analgesic pro-drug. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular hydrolases to amfenac, a non-steroidal anti-inflammatory drug. Amfenac inhibits the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.
Pharmacodynamic effects: The majority of hydrolytic conversion is in the retina/choroid followed by the iris/ciliary body and cornea, consistent with the degree of vascularized tissue. No significant effect on intraocular pressure has been reported in clinical trials (see Adverse Reactions).
Clinical Effects: In clinical studies conducted with Nepafenac 3 mg/ mL Eye Drops, Suspension, efficacy for prevention and treatment of postoperative pain and inflammation, was demonstrated in patients undergoing cataract surgery and for reducing the risk of postoperative macular edema was demonstrated in patients with diabetes undergoing cataract surgery.
Pediatric population: Nepafenac has not been studied in pediatric populations.
Pharmacokinetics: Absorption: For nepafenac 0.3% suspension, once daily dosing in both eyes after four days produced Cmax of 0.847 ng/mL for nepafenac and 1.13ng/mL for amfenac which was attained at 0.5 hours. The half-life for amfenac was approximately 5-fold longer in plasma than for nepafenac. The steady-state/single dose mean accumulation ratio was ≈ 1; therefore, no accumulation was observed for either nepafenac or amfenac after ocular dosing with nepafenac 0.3% suspension.
Distribution: Nepafenac and amfenac distributed to ocular tissues in rabbits after single topical dose with either 0.1% or 0.3% suspension. Higher concentrations were observed at site of dosing, cornea and conjunctiva and lower concentrations in posterior tissues, retina and choroid. Concentrations in ocular tissues increased with increased dose. When anterior ocular tissues concentrations were compared from a single dose of 0.3% nepafenac to that after three doses of 0.1% nepafenac in a single day, only the lens did not have a higher concentrations after the 0.3% nepafenac once a day dosing.
In cataract surgical patients, maximal aqueous humor concentrations were observed 1 hour following single dose of 0.1% nepafenac with a concentration of 177 ng/mL and 44.8 ng/mL for nepafenac and amfenac, respectively.
Plasma protein binding of nepafenac is moderate, ranging from 72.8% in rat plasma to 83.5% in human plasma. Protein binding was found to be concentration independent in rat, monkey and human plasma over a wide concentration range (10 to 1000 ng/mL). Amfenac is more highly bound at approximately 99%.
Biotransformation: Nepafenac undergoes relatively rapid in vivo hydrolysis to amfenac. After oral administration, unconjugated amfenac and nepafenac, and eight other metabolites were detected in plasma with amfenac, a pharmacological active metabolite having the highest concentration. Several of the metabolites were glucuronide conjugates based chromatographic shift after β-glucuronidase treatment. Nepafenac was detected in plasma but at relatively low levels (3.2% of total radioactivity). Amfenac was the major metabolite in plasma, representing approximately 13% of total plasma radioactivity. The second most abundant plasma metabolite was 5-hydroxy nepafenac in the form of a glucuronide, representing approximately 9.5% of total radioactivity at Cmax.
Neither nepafenac nor amfenac inhibit any of the major human cytochrome P-450 isozymes (CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) in vitro at concentrations up to 3000 and 1000 ng/mL, respectively.
After 14 days of oral administration, nepafenac does not increase CYP1A, CYP2B, CYP3A activities or total P450 content in rat, therefore no potential induction was observed for rat.
Elimination: After oral administration of 14C-nepafenac to healthy human volunteers, urinary excretion was found to be the major route of excreted radioactivity, accounting for approximately 85% while fecal represented approximately 6% of the dose out to 7 days.
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based upon conventional studies of safety Pharmacology, repeated dose toxicity or genotoxicity. Nepafenac has not been evaluated in long-term carcinogenicity studies.
Fertility and developmental and reproductive toxicity effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.