Optanep

Yellow coloured suspension (eye drops).
Each mL contains: Nepafenac 3 mg, Benzalkonium chloride 0.05 mg, Propylene glycol 8.00 mg.

Pharmacotherapeutic group: Non-steroidal Anti-inflammatory agents.
Pharmacology: Pharmacodynamics: Mechanism of action: Nepafenac is a non-steroidal 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 inhibits the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.
Secondary pharmacology: In rabbits, nepafenac has been shown to inhibit blood-retinal-barrier breakdown, concomitant with suppression of PGE2 synthesis. Ex vivo, a single topical ocular dose of nepafenac was shown to inhibit prostaglandin synthesis in the iris/ciliary body (85%-95%) and the retina/choroid (55%) for up to 6 hours and 4 hours, respectively.
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 vascularised tissue.
Results from clinical studies indicate that nepafenac eye drops have no significant effect on intraocular pressure.
Clinical efficacy and safety: Prevention and treatment of postoperative pain and inflammation associated with cataract surgery: The efficacy and safety of nepafenac in the prevention and treatment of postoperative pain and inflammation associated with cataract surgery has been demonstrated in two masked, double-blind, placebo-controlled clinical trials in a total of 1351 patients. In this study, patients were dosed daily beginning one day prior to cataract surgery, continued on the day of surgery, and for the first 14 days of the postoperative period. Nepafenac 3 mg/mL eye drops, suspension demonstrated superior clinical efficacy compared to its vehicle in treating postoperative pain and inflammation.
Patients treated with Nepafenac were less likely to have ocular pain and measurable signs of inflammation in the early postoperative period through to the end of treatment than those treated with its vehicle. In the two studies, Nepafenac cleared inflammation at day 14 post-operation in 65% and 68% of patients compared to 25% and 35% of patients on a vehicle. Pain-free rates in the Nepafenac group were 89% and 91% compared to 40% and 50% of patients on vehicles. Some patients received nepafenac 3 mg/mL eye drops, suspension for up to 21 days post operation. However, efficacy beyond day 14 post operation was not measured.
In addition, in one of the two clinical trials, nepafenac 3 mg/mL eye drops, suspension dosed once a day showed a similar effect with nepafenac 1 mg/mL eye drops, suspension dosed three times a day for the prevention and treatment of postoperative pain and inflammation following cataract surgery. Inflammation clearing and pain-free rates were similar for both products at all postoperative evaluations.
Pharmacokinetics: General Properties: Absorption: Following one drop of nepafenac 3 mg/mL eye drops, in both eyes once daily for four days, low but quantifiable plasma concentrations of nepafenac and amfenac were observed in the majority of subjects 2 and 3 hours post-dose, respectively. The mean steady-state plasma C_max for nepafenac and for amfenac was 0.847 ± 0.269 ng/mL and 1.13 ± 0.491 ng/mL, respectively, following ocular administration.
Distribution: Amfenac has a high affinity toward serum albumin proteins. In vitro, the percent bound to rat albumin, human albumin, and human serum was 98.4%, 95.4%, and 99.1%, respectively.
Studies in rats have shown that radioactively labeled active substance-related materials distribute widely in the body following single and multiple oral doses of 14C-nepafenac.
Biotransformation: Nepafenac undergoes relatively rapid bioactivation to amfenac via intraocular hydrolases. Subsequently, amfenac undergoes extensive metabolism to more polar metabolites involving hydroxylation of the aromatic ring leading to glucuronide conjugate formation.
Radiochromatographic analyses before and after β-glucuronidase hydrolysis indicated that all metabolites were in the form of glucuronide conjugates, with the exception of amfenac. Amfenac was the major metabolite in plasma, representing approximately 13% of total plasma radioactivity. The second most abundant plasma metabolite was identified as 5-hydroxy nepafenac, representing approximately 9% of total radioactivity at C_max.
Interactions with other medicinal products: Neither nepafenac nor amfenac inhibit any of the major human cytochrome P450 (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) metabolic activities in vitro at concentrations up to 3000 ng/mL. Therefore, interactions involving CYP-mediated metabolism of concomitantly administered medicinal products are unlikely. Interactions mediated by protein binding are also unlikely.
Elimination: After oral administration of 14C-nepafenac to healthy volunteers, urinary excretion was found to be the major route of radioactive excretions, accounting for approximately 85% while fecal excretion represented approximately 6% of the dose.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity.
Nepafenac has not been evaluated in long-term carcinogenicity studies.
In reproduction studies performed with nepafenac in rats, maternally toxic doses ≥10 mg/kg were associated with dystocia, increased post implantation loss, reduced fetal weights and growth, and reduced fetal survival. In pregnant rabbits, a maternal dose of 30 mg/kg that produced slight toxicity in the mothers showed a statistically significant increase in the incidence of litter malformations.

Nepafenac is indicated in adults for the prevention and treatment of postoperative pain and inflammation associated with cataract surgery.

Adults, including the elderly: For the prevention and treatment of pain and inflammation, the dose is 1 drop on the conjunctival sac of the affected eye(s) once a day beginning 1 day prior to cataract surgery, continued on the day of surgery, and for the first 2 weeks of the postoperative period. Treatment can be extended to the first 3 weeks of the postoperative period, as directed by the clinician. An additional drop should be administered 30 to 120 minutes prior to surgery.
For the reduction in the risk of postoperative macular edema associated with cataract surgery in diabetic patients, the dose is 1 drop of Nepafenac in the conjunctival sac of the affected eye(s) once daily beginning 1 day prior to cataract surgery, continued on the day of surgery and up to 60 days of the postoperative period as directed by the clinician.
An additional drop should be administered 30 to 120 minutes prior to surgery.
Once-daily dosing with Nepafenac 3 mg/mL eye drops, suspension provides the same total daily dose of Nepafenac as three-times-daily dosing with Nepafenac 1 mg/mL eye drops, suspension.
Special populations: Patients with renal or hepatic impairment: Nepafenac has not been studied in patients with hepatic disease or renal impairment. Nepafenac is eliminated primarily through biotransformation and the systemic exposure is very low following topical ocular administration. No dose adjustment is warranted in these patients.
Pediatric population: The safety and efficacy of Nepafenac in children and adolescents have not been established. No data are available. Its use is not recommended in these patients until further data become available.
Geriatric population: No overall differences in safety and effectiveness have been observed between elderly and younger patients.
May be taken as prescribed by the physician.
Method of administration: For ocular use.
Instruct the patients to shake the bottle well before use.
If more than one topical ophthalmic medicinal product is being used, the medicinal product must be administered at least 5 minutes apart. Eye ointments should be administered last.
To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas, or other surfaces with the dropper tip of the bottle. The bottle should be kept tightly closed when not in use.

No toxic effects are likely to occur in case of overdose with ocular use, nor in the event of accidental oral ingestion.

It is contraindicated in patients who have hypersensitivity to the active substance, any of the excipients, or other nonsteroidal anti-inflammatory drugs (NSAIDs).
Like other NSAIDs, Nepafenac is contraindicated in patients with urticaria, acute rhinitis, or asthma attacks precipitated by acetylsalicylic acid or other NSAIDs.

Do not inject. Instruct the patients not to swallow Nepafenac.
Instruct the patients to avoid sunlight during treatment with Nepafenac.
Nepafenac 3 mg/mL eye drops should not be used for reducing postoperative macular edema risk associated with cataract surgery because the safety and efficacy of this dose have not been studied.
Ocular effects: Use of topical NSAIDs may result in keratitis. In some susceptible patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration, or corneal perforation. These events may be sight-threatening. In patients with evidence of corneal epithelial breakdown, Nepafenac use should be immediately discontinued and should be monitored closely for corneal health.
Topical NSAIDs may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids increases the potential for healing problems. For this reason, caution is advised when Nepafenac is used concomitantly with corticosteroids, especially in patients with a high risk for the side effects described as follows.
Post-marketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse reactions which may become sight-threatening. Topical NSAIDs should be used with caution in these patients. Prolonged use of topical NSAIDs may increase the risk for occurrence and severity of corneal adverse reactions in patients.
There have been reports that ophthalmic NSAIDs may cause increased bleeding of ocular tissues (including blood in the front chamber of the eye) in conjunction with ocular surgery. Nepafenac should be used with caution in patients with known bleeding tendencies or who are receiving other medicinal products that prolong bleeding time.
An acute ocular infection may be masked by the topical use of anti-inflammatory medicines. NSAIDs do not have any antimicrobial properties. Caution is advised during the concomitant use of anti-infectives in case of ocular infection.
Contact lenses: Wearing contact lens is not recommended during the postoperative period following cataract surgery. Therefore, contact lenses should not be worn during treatment with Nepafenac.
Benzalkonium Chloride: Benzalkonium chloride is widely used as a preservative in ophthalmic products and has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since Nepafenac contains benzalkonium chloride, close monitoring is required with frequent or prolonged use.
Benzalkonium chloride may cause eye irritation. Avoid contact with soft contact lenses. Remove contact lenses before administration and wait at least 15 minutes to wear them. It is known that it causes discoloration of soft contact lenses.
Nepafenac contains propylene glycol. Propylene glycol may cause eye irritation.
Cross-sensitivity: There is a potential for cross-sensitivity of nepafenac to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs.
Effects on the ability to drive and use machines: Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines, such as the usage of any eye drop. If blurred vision occurs after administration, the patient must wait until the vision clears before driving or using machines.
Use in the Elderly: It has the same usage as in adults.

General recommendation: Pregnancy category: C, D in 3rd trimester.
Women of childbearing potential/Contraception: It is recommended that women with childbearing potential use a medically appropriate contraceptive method during their treatment with Nepafenac.
Pregnancy Period: There are no adequate data regarding the use of Nepafenac in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Since the systemic exposure is expected as negligible after treatment with Nepafenac, the risk during pregnancy could be considered low. Nevertheless, as inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonal/fetal development and/or parturition and/or postnatal development, it is not recommended for use during pregnancy.
Lactation Period: It is unknown whether Nepafenac is excreted in human milk or not. Animal studies have shown the excretion of Nepafenac in the milk of rats. However, no effects on the suckling child are anticipated since the systemic exposure of the breastfeeding woman to Nepafenac is negligible. Nepafenac can be used during the lactation period.
Fertility: There is no data on the effect of Nepafenac on reproductive ability.

Summary of the safety profile: In clinical studies involving 1300 patients using nepafenac 3 mg/mL eye drops, 3 side effects (eye pain, punctate keratitis, hypersensitivity) have been observed in 3 patients (0.2%). One patient (0.1%) discontinued due to an adverse reaction (hypersensitivity), while no placebo-treated patients in these same studies discontinued due to an adverse reaction.
Observed adverse reactions with the use of Nepafenac 1 mg/mL eye drops, suspension and may also be observed with the use of Nepafenac 3 mg/mL eye drops, suspension. In clinical studies involving 2314 patients receiving Nepafenac 1 mg/mL eye drops, the most common adverse reactions were punctate keratitis, foreign body sensation, and eyelid margin crusting which occurred in between 0.4% and 0.2% of patients.
The following adverse reactions are evaluated according to the treatment and classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions were obtained from clinical trials and post-marketing reports.
Immune system disorders: Rare: Hypersensitivity.
Nervous system disorders: Rare: Dizziness, headache.
Eye disorders: Uncommon: keratitis, punctuate keratitis, corneal epithelium defect, foreign body sensation in the eye, eyelid margin crusting.
Rare: Iritis, choroidal effusion, corneal deposits, eye pain, ocular discomfort, dry eye, blepharitis, eye irritation, eye pruritus, watering of eyes, allergic conjunctivitis, increased lacrimation, conjunctival hyperemia.
Not known: impaired healing (cornea), corneal opacity, corneal scar, reduced visual acuity, eye irritation, eye swelling, ulcerative keratitis, corneal thinning, blurred vision.
Vascular disorders: Not known: Increase in blood pressure.
Gastrointestinal disorders: Rare: Nausea.
Not known: Vomiting.
Skin and subcutaneous tissue disorders: Rare: Cutis laxa (as a result of thickening, skin shows sagging in the form of folds) allergic dermatitis.
Not Known: Increase in blood pressure.
Description of selected adverse effects: Patients with evidence of corneal epithelial breakdown should immediately discontinue the use of Nepafenac and should be monitored closely for corneal health.
From post-marketing experience with Nepafenac 1 mg/mL eye drops, cases reporting corneal epithelium defect/disorder have been identified. Severity of these cases varies from non-serious effects on the epithelial integrity of the corneal epithelium to more serious events where surgical interventions and/or medical therapy are required to regain clear vision.
Post-marketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse reactions which may become sight-threatening.
Pediatric population: The safety and efficacy of Nepafenac in children and adolescents have not been established.

In vitro studies have demonstrated a very low potential for interaction with other medicinal products and protein-binding interactions.
Prostaglandin analogues: There is very limited data about concomitant use of Nepafenac and analogues of prostaglandin. When their action mechanisms are taken into consideration, concomitant use of these medicinal drugs should not be recommended.
Concomitant use of topical NSAIDs and topical steroids may retard healing. Concomitant use of Nepafenac with medications that prolong bleeding time may increase the risk of hemorrhage.
Additional data for special populations: Interaction studies have not been performed.
Pediatric population: Interaction studies have not been performed.

Special Precautions for Disposal and Other Handling: Any unused product or waste material should be disposed of in accordance with local requirements.
Shake before use.
After opening the bottle, avoid contamination and the tip of the bottle should not be touched anywhere. After use, the cap should be closed.
4 weeks after opening the bottle, discard the remaining solution.

Store at temperatures not exceeding 30°C.

Ophthalmic Decongestants, Anesthetics, Anti-Inflammatories

S01BC10 - nepafenac ; Belongs to the class of non-steroidal antiinflammatory agents. Used in the treatment of inflammation of the eye.

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