Instructions Nevanac eye drops suspension 1 mg/ml dropper bottle drop-tainer 5 ml
Composition
active substance: nepafenac; 1 ml of suspension contains 1 mg nepafenac;
excipients: benzalkonium chloride, carbomer 974P, tyloxapol, disodium edetate dihydrate, mannitol (E 421), sodium chloride, sodium hydroxide and/or concentrated hydrochloric acid (for pH adjustment), purified water.
Dosage form
Eye drops.
Main physicochemical properties: homogeneous suspension from light yellow to light orange.
Pharmacotherapeutic group
Drugs used in ophthalmology. Nonsteroidal anti-inflammatory drugs. Nepafenac. ATX code S01B C10.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Nepafenac is a nonsteroidal anti-inflammatory and analgesic prodrug. After topical application to the eye, nepafenac penetrates the cornea and is converted by ocular tissue hydrolase 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 animal studies, nepafenac was shown to reduce the permeability of the blood-retinal barrier in rabbits while inhibiting PGE2 (prostaglandin E2) synthesis. In ex vivo studies, a single dose of nepafenac topically administered to the eye inhibited prostaglandin synthesis in the iris/ciliary body (85-95%) and retina/choroid (55%) for up to 6 hours and 4 hours, respectively.
Pharmacodynamic properties
Most hydrolytic transformations occur in the retina/choroid, followed by the iris/ciliary body and cornea, depending on the degree of vascularization of the tissue.
Clinical trial results indicate that Nevanac® eye drops do not have a significant effect on intraocular pressure.
Clinical effects
Prevention and treatment of postoperative pain and inflammation associated with cataract surgery.
Three main studies were conducted to evaluate the efficacy and safety of Nevanac® (1 drop in the conjunctival sac of the affected eye(s) 3 times daily) compared with placebo and/or ketorolac trometamol for the prevention and treatment of postoperative pain and inflammation in patients undergoing cataract surgery. The studies started 1 day before surgery, continued on the day of surgery, and continued for 2–4 weeks postoperatively. In addition, nearly all patients received prophylactic antibiotics in accordance with clinical practice at each trial site.
In two double-blind, randomized, placebo-controlled studies, patients treated with Nevanac® had significantly less inflammation (precipitates in the intraocular fluid and opalescence) during the early postoperative period and until the end of treatment than patients treated with placebo.
In one double-blind, randomized, placebo-controlled, active-controlled trial, patients treated with Nevanac® had significantly less inflammation than those treated with placebo. Nevanac® was also non-inferior to ketorolac 5 mg/ml in reducing ocular pain and inflammation and was more convenient to instill.
A significantly higher percentage of patients treated with Nevanac® reported no eye pain after cataract surgery compared to patients treated with placebo.
Reducing the risk of postoperative macular edema associated with cataract surgery in patients with diabetes.
Three studies (one in diabetic patients and two in non-diabetic patients) were conducted to evaluate the efficacy and safety of Nevanac® for the prevention of macular edema after cataract surgery. The studies included administration 1 day before surgery, on the day of surgery, and for up to 90 days postoperatively.
In one double-blind, randomized, placebo-controlled study in patients with diabetic retinopathy, macular edema was observed significantly more frequently in patients treated with placebo (16.7%) than in patients treated with Nevanac® (3.2%). A greater percentage of patients treated with placebo experienced a decrease in best-corrected visual acuity of more than 5 lines from day 7 to day 90 (or at early study discontinuation) (11.5%) compared to patients treated with Nevanac® (5.6%). A greater proportion of patients treated with Nevanac® achieved an improvement in best-corrected visual acuity of 15 lines compared to patients treated with placebo, 56.8% versus 41.9%, respectively, p=0.019.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, and genotoxicity.
Long-term studies of the carcinogenic properties of nepafenac have not been conducted.
In a reproductive toxicity study in rats, nepafenac was shown to cause dystocia, increased risk of post-implantation loss, decreased body weight and growth retardation, and decreased fetal survival at maternally toxic doses of ≥10 mg/kg. Administration of 30 mg/kg to pregnant rabbits, which resulted in minor toxicity in rabbits, resulted in a statistically significant increase in the incidence of fetal malformations.
Pharmacokinetics
Absorption
After instillation of Nevanac® eye drops 3 times daily into both eyes, the plasma concentrations of nepafenac and amfenac in most patients were low but quantifiable at 2 and 3 hours post-application, respectively. The mean steady-state plasma concentrations of nepafenac and amfenac after topical administration were 0.310±0.104 ng/mL and 0.422±0.121 ng/mL, respectively.
Distribution
Amfenac has a high affinity for serum albumin. In vitro, the percentage bound to rat albumin, human albumin and human serum was 98.4%, 95.4% and 99.1%, respectively.
A study in rats showed that after oral administration of a single or multiple dose of 14C-nepafenac, radiolabeled substances associated with the active substance of the drug are distributed throughout the body.
Biotransformation
Nepafenac is relatively rapidly bioactivated to amfenac by an intraocular hydrolase. Amfenac is then extensively metabolized to more polar metabolites, including hydroxylation of the aromatic ring, resulting in the formation of a glucuronide conjugate. Radiochromatographic analysis before and after β-glucuronidase hydrolysis showed that all metabolites were in the form of glucuronide conjugates, except for amfenac. Amfenac was the predominant metabolite in plasma, accounting for approximately 13% of the total plasma radioactivity. The second most abundant metabolite in plasma was 5-hydroxynepafenac, accounting for approximately 9% of the total radioactivity at Cmax.
Interactions with other drugs: In humans, nepafenac and amfenac do not inhibit the metabolism of the major cytochromes P450 (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) in vitro at concentrations up to 300 ng/mL. Therefore, interactions related to CYP-mediated metabolism of other concomitantly administered drugs are unlikely. Interactions mediated by protein binding are also unlikely.
Breeding
Following oral administration of 14C-nepafenac to healthy volunteers, the substance was excreted primarily in the urine, approximately 85%, while only about 6% of the dose was excreted through the intestines. The amount of nepafenac and amfenac in the urine was not quantifiable.
After a single dose of Nevanac® was administered to 25 patients undergoing cataract surgery, the concentration of the substances in the intraocular fluid was measured 15, 30, 45 and 60 minutes after administration. The maximum concentration of the substance in the intraocular fluid was observed after 1 hour (nepafenac concentration was 177 ng/ml, amfenac concentration – 44.8 ng/ml). These data indicate a rapid penetration of the active substance of the drug into the cornea.
Indication
Nevanac® is used in adults for:
prevention and treatment of pain and inflammation after cataract surgery; reduction of the risk of macular edema after cataract surgery in patients with diabetes mellitus (see section "Pharmacodynamics").
Contraindication
Hypersensitivity to the active substance, any of the components of the drug or other non-steroidal anti-inflammatory drugs (NSAIDs).
Nevanac® is contraindicated in patients in whom the use of acetylsalicylic acid or other NSAIDs causes asthma attacks, urticaria, or acute rhinitis.
Interaction with other medicinal products and other types of interactions
Concomitant use of topical NSAIDs and steroids may impair wound healing. Concomitant use of Nevanac® with drugs that increase blood clotting time increases the risk of bleeding.
In vitro studies have demonstrated a very low probability of interaction with other drugs and the possibility of binding to plasma proteins.
Prostaglandin analogues.
There are very limited data on the concomitant use of prostaglandin analogues and Nevanac®. Given their mechanism of action, concomitant use of these medicinal products is not recommended.
Application features
Topical NSAIDs may cause keratitis. In some susceptible patients, prolonged use of topical NSAIDs may result in epithelial damage, corneal thinning, corneal erosion, corneal ulceration, or corneal perforation. These events may result in loss of vision. Patients who develop signs of corneal epithelial damage should immediately discontinue Nevanac® and have their corneas examined.
Topical NSAIDs may slow or delay wound healing. Topical corticosteroids are also known to slow or delay wound healing. Concomitant use of topical NSAIDs and steroids may complicate wound healing.
Post-marketing experience with topical NSAIDs suggests that patients who have undergone repeated and/or complex ophthalmic surgery, patients with corneal denervation, patients with corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g. dry eye syndrome), and rheumatoid arthritis are at increased risk of corneal adverse reactions that may lead to vision loss. NSAIDs should be used with caution in such patients. Long-term use of topical NSAIDs may increase the risk and severity of corneal adverse reactions.
It has been reported that the concomitant use of NSAIDs in ophthalmology and ophthalmic surgery may cause severe bleeding into the ocular tissues (including hyphema). Nevanac® should be used with particular caution in patients with a known tendency to bleed or those who are currently taking other medications that may increase bleeding time.
There are very limited data on the concomitant use of Nevanac® with prostaglandin analogues. Given their mechanism of action, concomitant use of these drugs is not recommended.
Nevanac® contains benzalkonium chloride, which may cause eye irritation and discolour soft contact lenses. In addition, contact lenses are not recommended for use after cataract surgery.
Patients should be advised not to wear contact lenses during treatment with Nevanac®. If contact lenses are required during treatment, patients should be advised to remove contact lenses prior to application of the medicinal product and wait at least 15 minutes before reinsertion.
Benzalkonium chloride, a widely used preservative in ophthalmic medicinal products, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since Nevanac® contains benzalkonium chloride, close monitoring should be performed with frequent or prolonged use.
Topical anti-inflammatory drugs may mask the development of an acute eye infection. NSAIDs do not have any antimicrobial properties. In the event of an eye infection, NSAIDs should be used with extreme caution in conjunction with antibacterial agents.
Use in patients with impaired liver and kidney function
The use of Nevanac® in patients with impaired liver and kidney function has not been studied. Nepafenac is eliminated from the body mainly by biotransformation, and systemic effects on the body after topical application are very insignificant. There is no need for dose adjustment for this category of patients.
Cross-sensitivity
Cross-sensitivity between nepafenac and acetylsalicylic acid, phenylacetic acid derivatives and other NSAIDs is possible.
Ability to influence reaction speed when driving vehicles or other mechanisms
As with other eye drops, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs during instillation, the patient should wait until vision clears before driving or operating machinery.
Use during pregnancy or breastfeeding
Reproductive function
There are no data on the effect of Nevanac® on human reproductive function.
The drug Nevanac® should not be used in women of reproductive age who are not using adequate contraception.
Pregnancy
There are no adequate data on the use of the drug in pregnant women. Animal studies have shown reproductive toxicity (see section "Pharmacological properties"). The potential risk to human reproductive function is unknown. Since the systemic effect of Nevanac® on the body of non-pregnant women is insignificant, the risk of using this drug during pregnancy can be considered low. However, since the delay in prostaglandin synthesis may adversely affect pregnancy and/or embryo/fetal development, and/or childbirth, and/or postnatal development, the use of Nevanac® is not recommended during pregnancy and in women of childbearing potential not using contraceptives.
It is not known whether nepafenac is excreted in human milk. Animal studies have shown that nepafenac is excreted in rat milk. However, no adverse effects on the infant are expected, as systemic exposure to nepafenac in the breast-feeding woman is very low. Therefore, Nevanac® can be used during breast-feeding.
Method of administration and doses
Use in adults, including elderly patients
Do not exceed the recommended dosage.
To prevent and treat pain and inflammation, instill 1 drop of Nevanac® into the conjunctival sac of the affected eye(s) 3 times daily, starting 1 day before cataract surgery, then on the day of surgery, and for up to 21 days postoperatively as directed by your doctor. An additional drop should be applied 30–120 minutes before surgery.
To reduce the risk of macular edema after cataract surgery in patients with diabetes, instill 1 drop of Nevanac® into the conjunctival sac of the affected eye(s) 3 times daily, starting 1 day before cataract surgery, then on the day of surgery, and for up to 60 days postoperatively as directed by your physician. An additional drop should be applied 30–120 minutes before surgery.
Method of application
For ophthalmic use.
The patient should be informed of the need to shake the bottle thoroughly before use.
If several topical eye medications are used simultaneously, the interval between their applications should be at least 5 minutes.
To prevent contamination of the dropper tip and solution, do not touch the eyelids, surrounding areas, or other surfaces with the dropper tip. Keep the bottle tightly closed when not in use.
Children
The safety and effectiveness of Nevanac® in children have not been established, therefore the drug is not recommended for use in children.
Overdose
There is no data on overdose of the drug when instilled into the eyes. There is a very small probability that the use of more than 1 drop in the eye will lead to adverse reactions. Adverse reactions are not expected to occur if the drug is accidentally swallowed.
Adverse reactions
In clinical trials involving 800 patients treated with Nevanac®, adverse reactions occurred in approximately 3% of patients. These led to discontinuation of the drug in 0.6% of patients, which was lower than in the placebo group (1.3%). The most common adverse reactions in clinical trials were keratitis, eye pain, and eyelid margin scaling, which occurred in 0.5% of patients.
The following adverse reactions, which were considered to be associated with the use of Nevanac® in clinical trials, are classified as follows: 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), rare (<1/10,000). Within each grouping, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions according to MedDRA classification
Immune system disorders
Rare: hypersensitivity.
Nervous system disorders
Uncommon: dizziness, headache.
Ophthalmological disorders
Uncommon: keratitis, punctate keratitis, corneal epithelial defect, allergic conjunctivitis, eye pain, foreign body sensation in the eye, eyelid margin scaling.
Rare: blurred vision, photophobia, dry eye, blepharitis, eye itching, eye discharge, lacrimation increased, iritis, choroidal effusion, corneal deposits, ocular discomfort, conjunctival hyperemia.
Gastrointestinal disorders
Uncommon: nausea.
Skin and subcutaneous tissue disorders.
Rare: dermatochalasis, allergic dermatitis.
The following additional adverse reactions have been identified during post-marketing surveillance. The frequency of their occurrence cannot be estimated from the available data. Within each system organ class, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions according to MedDRA classification
Ophthalmological disorders: ulcerative keratitis, corneal thinning, corneal opacity, corneal scar, impaired healing process (cornea), decreased visual acuity, eye swelling, eye irritation, eye hyperemia;
Gastrointestinal disorders: vomiting;
Laboratory tests: elevated blood pressure.
Patients with diabetes
The following adverse reactions have been considered to be associated with the use of Nevanac®; they are classified as follows: 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) or rare (<1/10,000). Within each grouping, adverse reactions are presented in order of decreasing seriousness.
Ophthalmological disorders
Common: punctate keratitis.
Uncommon: corneal epithelial defect.
Certain side effects
Clinical experience with long-term use of Nevanac® for the prevention of macular edema after cataract surgery in patients with diabetes mellitus is limited. Ocular adverse reactions may occur more frequently in patients with diabetes mellitus than in other patient categories (see section "Special warnings and precautions for use").
Patients who show signs of corneal epithelial damage should immediately discontinue use of Nevanac® and have their corneas examined (see section 4.4).
Post-marketing reports of corneal epithelial damage/disruption have been received with Nevanac® eye drops. The severity of these adverse events ranges from minor disruption of the integrity of the corneal epithelium to more serious events requiring surgical intervention and/or treatment to restore visual acuity.
Based on post-marketing experience with topical NSAIDs, patients undergoing complex ophthalmic surgery, patients with corneal denervation, patients with corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g. dry eye syndrome), rheumatoid arthritis, and patients undergoing repeated ophthalmic surgeries at short intervals are at risk for corneal adverse reactions that may lead to vision loss. When prescribing nepafenac to diabetic patients to prevent macular edema after cataract surgery and in the presence of other risk factors, the benefit/risk ratio should be re-evaluated and the patient should be closely monitored.
Expiration date
2 years.
Shelf life after first opening the bottle is 4 weeks.
Storage conditions
Store at a temperature not exceeding 30 °C.
Keep out of reach of children.
Packaging
5 ml in a Drop-Tainer® dropper bottle; 1 bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
Alcon-Couvreur.
Location of the manufacturer and its business address
Rijksweg 14, B-2870 Poort, Belgium.
