Nevanac^® (Drops) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Alcon-Couvreur N.V., S.A. (Belgium)

Contact Information

NOVARTIS PHARMA LLC (Russia)

ATC Code

S01BC10 (Nepafenac)

Active Substance

Nepafenac (Rec.INN registered by WHO)

Dosage Form

Nevanac®

Eye drops 1 mg/1 ml: dropper bottle 5 ml

Dosage Form, Packaging, and Composition

Eye drops as a homogeneous suspension from light yellow to light orange in color.

Excipients: benzalkonium chloride, carbomer (974P), tyloxapol, disodium edetate, mannitol, sodium chloride, sodium hydroxide and/or hydrochloric acid, purified water.

5 ml – dropper bottles made of low-density polyethylene (1) – cardboard packages.

The presence of a first-opening control on the cardboard package is allowed.

Clinical-Pharmacological Group

NSAIDs for topical use in ophthalmology

Pharmacotherapeutic Group

Agents used in ophthalmology; anti-inflammatory agents; nonsteroidal anti-inflammatory agents

Pharmacological Action

Mechanism of action

Nepafenac is a prodrug of the active form of nonsteroidal medicinal products with anti-inflammatory and analgesic action. When applied topically, Nepafenac penetrates the cornea of the eye, where it is converted by hydrolases into amfenac, the active form. Amfenac inhibits the action of prostaglandin-H-synthase (cyclooxygenase), an enzyme necessary for the production of prostaglandin.

Secondary pharmacological effect

In rabbits, Nepafenac reduces the permeability of the blood-retinal barrier while inhibiting the synthesis of PGE₂. Under ex vivo conditions, it was confirmed that a single dose of nepafenac applied topically suppresses 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 of the hydrolytic conversion occurs in the retina/choroid, as well as in the iris/ciliary body and cornea, depending on the degree of tissue vascularization.

Results of clinical studies indicate that Nevanac^® does not have a significant effect on IOP.

Clinical efficacy and safety

Prevention and treatment of pain and inflammation in the postoperative period after cataract extraction

Three pivotal studies were conducted to evaluate the efficacy and safety of Nevanac^® when applied 3 times/day compared with placebo and/or ketorolac tromethamine in the prevention and treatment of pain and inflammation in patients in the postoperative period after cataract extraction. In these studies, the use of the study drug began 1 day before surgery, continued on the day of surgery and up to 2-4 weeks postoperatively. Additionally, almost all patients received prophylactic antibiotic treatment, in accordance with clinical practice at each study center.

In two double-blind, randomized, placebo-controlled studies, patients receiving Nevanac^® had significantly less pronounced inflammation (cells and aqueous flare) from the early postoperative period until the end of treatment than patients receiving placebo.

In one double-blind, randomized, placebo-controlled and active-controlled study, patients receiving Nevanac^® had significantly less pronounced inflammation than patients receiving placebo. Furthermore, Nevanac^® was not inferior to ketorolac 5 mg/ml in reducing ocular inflammation and pain and was significantly more comfortable upon instillation.

In the Nevanac^® group, cases of absence of ocular pain in the postoperative period after cataract extraction were recorded in a significantly greater percentage of patients than in the placebo group.

Reducing the risk of macular edema in patients with diabetes mellitus in the postoperative period after cataract extraction

To evaluate the efficacy and safety of Nevanac^® when used for the prevention of postoperative macular edema associated with cataract extraction surgery, 4 studies were conducted (2 – among patients with diabetes mellitus and 2 – among patients without diabetes mellitus). In these studies, the use of the study drug began 1 day before surgery, continued on the day of surgery and up to 90 days postoperatively.

In one double-blind, randomized, placebo-controlled study conducted among patients with diabetic retinopathy, macular edema developed in a significantly greater percentage of patients in the placebo group (16.7%) compared to the group of patients who used Nevanac^® (3.2%). A greater proportion of patients receiving placebo experienced a decrease in best-corrected visual acuity by more than 5 letters from day 7 to day 90 (or premature discontinuation in the placebo group) (11.5%) compared to patients using Nepafenac (5.6%). An improvement of 15 letters in best-corrected visual acuity was observed in a greater proportion of patients using Nevanac^® compared to patients taking placebo, 56.8% versus 41.9% respectively, p=0.019.

Preclinical safety data

In preclinical data obtained from standard studies of pharmacological safety, repeated dose toxicity and genotoxicity, no particular hazard to humans was identified.

Nepafenac has not been studied in long-term carcinogenicity studies.

Information on toxic effects on reproductive function is provided in the section “Pregnancy and lactation”.

Pharmacokinetics

Absorption

After three times daily instillation of Nevanac^® into both eyes, low but quantifiable concentrations of nepafenac and amfenac were detected in plasma after 2 and 3 hours, respectively. The C_max of nepafenac in plasma after topical application as instillations into the conjunctival sac is 0.310±0.104 ng/ml; C_max of amfenac is 0.422±0.121 ng/ml.

The C_max of nepafenac in the aqueous humor is observed on average after 1 hour.

Distribution

Nevanac^® is rapidly absorbed through the cornea of the eye.

After application of a single dose of Nevanac^® in 25 patients with cataract, measurement of aqueous humor concentration was performed at 15, 30, 45 and 60 minutes after dose application. The maximum mean aqueous humor concentration was observed at the 1-hour time point (Nepafenac 177 ng/ml, amfenac 44.8 ng/ml). The data indicate rapid penetration through the cornea.

Amfenac has a high affinity for serum albumin. In vitro binding to rat albumin, human albumin and human serum was 98.4%, 95.4% and 99.1%, respectively.

Studies in rats have shown that radiolabeled substances associated with the active substance are widely distributed in the body after single and repeated oral administration of ¹⁴C-nepafenac.

Metabolism

When applied topically, under the action of intraocular hydrolases, Nepafenac undergoes rapid hydrolysis to amfenac.

Further metabolism of amfenac proceeds by hydroxylation of the aromatic ring, leading to the formation of glucuronic acid conjugates. Radiochromatographic analysis performed before and after hydrolysis with β-glucuronidase showed that all metabolites were present as glucuronic acid conjugates, except for amfenac. Amfenac was the main metabolite in plasma – this substance accounted for about 13% of the total radioactivity detected in plasma. The second most common metabolite in plasma was 5-hydroxynepafenac with 9% of total radioactivity at C_max.

Elimination

Elimination studies were conducted in both healthy volunteers and patients in the postoperative period after cataract extraction.

After oral administration of ¹⁴C-nepafenac to healthy volunteers, about 85% of the radioactivity after oral administration of ¹⁴C-nepafenac is found in urine and about 6% in feces. Concentrations of nepafenac and amfenac in urine are not quantifiable.

Indications

• Prevention and treatment of pain and inflammation in the postoperative period after cataract extraction;
• Reducing the risk of macular edema in patients with diabetes mellitus in the postoperative period after cataract extraction.

ICD codes

Dosage Regimen

Adults, including elderly patients

Prevention and treatment of pain and inflammation in the postoperative period after cataract extraction

1 drop of Nevanac^® into the conjunctival sac of the affected eye(s) 3 times/day. Treatment is started 1 day before cataract surgery, continued on the day of surgery and during the first 2 weeks of the postoperative period. An additional drop of the drug should be instilled 30-120 minutes before surgery.

Treatment may be extended up to 3 weeks postoperatively as prescribed by a physician.

Reducing the risk of macular edema in patients with diabetes mellitus in the postoperative period after cataract extraction

1 drop of Nevanac^® into the conjunctival sac of the affected eye(s) 3 times/day. Treatment is started 1 day before cataract surgery, then continued on the day of surgery and in the postoperative period for up to 60 days as prescribed by a physician.

An additional drop of the drug should be instilled 30-120 minutes before surgery.

Special patient groups

Elderly patients (65 years or older)

No differences in safety and efficacy between elderly patients and younger patients were identified.

Patients with impaired liver and kidney function

The use of Nevanac^® in patients with impaired liver and kidney function has not been studied. There is no need for dose adjustment for this category of patients, since after topical application, as instillations into the conjunctival sac, its systemic exposure is very low.

Children

The safety and efficacy of Nevanac^® in children and adolescents have not been established. No data available. The use of Nevanac^® in patients of this age group is not recommended until additional data are obtained.

Method of administration

Topically, as instillations into the conjunctival sac. Shake the bottle thoroughly before use.

After removing the cap, if the snap-on ring with tamper evidence is not attached to the neck, it must be removed before using the drug.

Do not touch the tip of the dropper bottle to any surface to avoid contamination of the dropper bottle and its contents. Also avoid contact of the dropper bottle tip with the eye, as such contact may injure the eye.

Keep the bottle tightly closed when not in use.

When using several topical ophthalmic medicinal products, they should be instilled at least 5 minutes apart. Eye ointments should be applied last.

If a dose of the drug is missed, 1 drop should be instilled as soon as possible, before returning to the usual dosing regimen. A missed dose should not be compensated for by doubling the dose.

Adverse Reactions

Summary of the safety profile

In clinical studies involving 2314 patients who used Nevanac^® 1 mg/ml, the most common adverse reactions (ARs) were punctate keratitis, foreign body sensation in the eye, and eyelid margin crusting, which were observed in 0.2-0.4% of patients.

Tabulated summary of adverse reactions

The ARs listed below are presented according to the affected organ systems and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). Within each frequency group, adverse events are presented in order of decreasing severity.

Information on ARs was obtained from clinical studies and during post-registration use of the drug.

Patients with diabetes mellitus

During two clinical studies involving 209 patients, patients with diabetes mellitus were treated with Nevanac^® for 60 days or more to prevent macular edema in the postoperative period after cataract extraction. The most common AR was punctate keratitis, noted in 3% of patients (frequency category – common). Other reported ARs were corneal epithelial defect and allergic dermatitis, noted in 1% and 0.5% of patients, respectively (frequency category – uncommon).

Description of selected adverse reactions

Experience with long-term clinical use of Nevanac^® for the prevention of macular edema associated with cataract extraction surgery in patients with diabetes is limited. ARs related to the eye in patients with diabetes may occur more frequently than in the general population (see section “Special warnings and precautions for use”).

In patients with signs of corneal epithelial impairment, including corneal perforation, the use of Nevanac^® should be discontinued immediately and careful monitoring of the corneal condition is also necessary (see “Special warnings and precautions for use”).

During the post-registration experience with Nevanac^®, cases of corneal epithelial defect/corneal disorders have been reported. The severity of these cases ranged from mild effects on corneal epithelial integrity to more serious reactions requiring surgical intervention and/or the use of additional medications to restore visual clarity.

Post-registration experience with topical NSAIDs indicates that patients after complex eye surgeries, with corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or after repeated eye surgeries within a short period of time have an increased risk of developing corneal adverse reactions that may be vision-threatening.

When prescribing Nevanac^® to patients with diabetes mellitus after cataract extraction surgery to prevent macular edema, the presence of any additional risk factor requires a reassessment of the expected benefit/risk ratio and more intensive patient monitoring.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients included in the drug, as well as to other NSAIDs;
• Bronchial asthma, urticaria, acute rhinitis caused by taking acetylsalicylic acid or other NSAIDs.

Use in Pregnancy and Lactation

Pregnancy

No reliable and well-controlled studies have been conducted in pregnant women that would allow conclusions to be drawn about the drug-related risk. Data on the use of Nevanac^® in pregnant women are limited.

In studies of embryofetal toxicity in rats and rabbits, Nepafenac, administered orally during the period of organogenesis, did not cause embryofetal toxicity at a dose of 10 mg/kg/day (which, when converted to human exposure to nepafenac and amfenac, exceeds the MRHD, which is 1 drop of Nevanac^®, eye drops 0.3%, in each eye, by 20 and 179 times, respectively).

Oral administration of nepafenac to pregnant rats during gestation and lactation caused death of pregnant females at all doses, including the minimum studied dose of 3 mg/kg/day.

The no observed effect level (NOEL) for maternal toxicity in this study was not established. When the drug was used at doses ≥3 mg/kg/day, dystocia was noted, and when used at doses ≥10 mg/kg/day, an increased frequency of offspring death was noted, especially in the early neonatal period.

Since systemic exposure in humans after application of Nevanac^® is negligible (<1 ng/ml), the risk associated with the use of the drug during pregnancy can be considered low. However, inhibition of prostaglandin synthesis may have an adverse effect on the course of pregnancy, embryonic/fetal development, labor and (or) postnatal development.

Pregnant women should be warned about the possible risk to the fetus. Nevanac^® should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.

Breastfeeding

Data on the presence of nepafenac in breast milk, its effect on the breastfed child, or on milk production are absent. After administration, Nepafenac passes into the milk of lactating rats; the milk-to-plasma concentration ratio is < 0.6. It is not known whether Nepafenac will be detected in human breast milk after topical administration into the conjunctival sac.

Along with the benefits of breastfeeding for the child’s development and health, the medical necessity of using Nevanac^® for the mother, as well as the potential adverse effect of Nevanac^® on the breastfed child, should be taken into account.

Fertility

Data on the effect of nepafenac on human fertility are absent.

In studies in rats receiving the drug at doses above 3 mg/kg/day (which, based on the exposure to nepafenac and amfenac in humans, exceeds the Maximum Recommended Human Ophthalmic Dose (MRHOD) by 17 and 351 times, respectively), no significant effect on fertility was identified.

In a fertility study, rats were administered the drug orally at doses of 3, 10, 15, and 30 mg/kg/day. Animals receiving the drug at a dose of 30 mg/kg/day were euthanated prematurely due to excessive toxicity. In animals receiving the drug at a dose of 15 mg/kg/day, a decrease in sperm motility and concentration (in males) was observed in the absence of any microscopic changes in the testes and epididymides. No significant changes in mating and fertility parameters were noted. At doses of 10 and 15 mg/kg/day, a decrease in the number of viable fetuses and an increase in the number of early resorptions were observed. The No Observed Effect Level (NOEL) for reproductive toxicity in males and females was 3 mg/kg/day, which, based on the exposure to nepafenac and amfenac in humans, exceeds the MRHOD by 17 and 351 times, respectively.

Use in Hepatic Impairment

The use of Nevanac^® in patients with impaired liver function has not been studied. Dosage adjustment for this category of patients is not necessary, since after topical administration into the conjunctival sac, its systemic exposure is very low.

Use in Renal Impairment

The use of Nevanac^® in patients with impaired renal function has not been studied. Dosage adjustment for this category of patients is not necessary, since after topical administration into the conjunctival sac, its systemic exposure is very low.

Pediatric Use

Contraindicated in children under 18 years of age (the safety and efficacy of Nevanac^® in children and adolescents have not been established).

Geriatric Use

No differences in safety and efficacy between elderly patients and younger patients have been identified.

Special Precautions

Nevanac^® is not intended for injectable administration. Patients should be warned that the drug should not be taken orally.

Patients should avoid exposure to sunlight while using Nevanac^®.

Ophthalmic Effects

The use of topical (ophthalmic) NSAIDs may lead to keratitis. In some susceptible patients, long-term use of topical (ophthalmic) NSAIDs may cause corneal epithelial cell breakdown, corneal thinning, corneal erosion, corneal ulceration, or corneal perforation (see the “Adverse Reactions” section). These adverse reactions may pose a risk of vision loss. Patients with corneal epithelial breakdown should immediately discontinue the use of Nevanac^® and be monitored for the condition of the cornea.

The use of topical (ophthalmic) NSAIDs may slow or delay the healing process. Topical (ophthalmic) corticosteroids are also known to slow or delay healing. Concomitant use of topical (ophthalmic) NSAIDs and topical (ophthalmic) corticosteroids may increase the likelihood of healing problems.

Post-marketing experience with topical (ophthalmic) NSAIDs suggests that patients with complications following ophthalmic surgical procedures, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeated surgical interventions performed within a short period of time may have an increased risk of corneal adverse reactions, which may threaten vision loss. Topical (ophthalmic) NSAIDs should be used with caution in such patients. Long-term use of these drugs may increase the risk and severity of corneal adverse reactions.

The use of topical (ophthalmic) NSAIDs in conjunction with eye surgery may cause increased bleeding in the eye tissues (including hyphema). Nevanac^® should be used with caution in patients with a history of bleeding tendencies or in patients receiving other medications that may prolong bleeding time.

The use of topical (ophthalmic) NSAIDs may hinder the timely recognition of signs of an acute eye infection. NSAIDs do not possess any antimicrobial properties. If an eye infection develops, the use of topical NSAIDs concomitantly with antibacterial agents should be done with caution.

Data on the concomitant use of prostaglandin analogs and Nevanac^® are absent. Given their mechanisms of action, concomitant use is not recommended.

Contact Lenses

The use of contact lenses is not recommended during the postoperative period after cataract surgery.

Excipients

Nevanac^® contains the preservative benzalkonium chloride, which may cause eye irritation and discoloration of soft contact lenses. It is not recommended to use contact lenses while being treated with Nevanac^®. If contact lens use is necessary during treatment, patients should be informed that they should remove their contact lenses before instilling Nevanac^® and wait at least 15 minutes after instillation before reinserting them.

Studies have shown that benzalkonium chloride, contained in Nevanac^®, can cause punctate keratitis and/or toxic ulcerative keratopathy. Therefore, with frequent or prolonged use of the drug, careful medical supervision of the patient is necessary.

Cross-Sensitivity

When using nepafenac, there is a possibility of cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs.

Effect on Ability to Drive and Operate Machinery

After using the drug, a temporary decrease in visual acuity may occur, and until it is restored, it is not recommended to drive a car or engage in activities requiring increased attention and quick reactions.

Overdose

Data on drug overdose are absent.

In case of overdose due to ophthalmic use or in case of unintentional oral ingestion, no adverse reactions are expected.

If an excessive amount of the drug gets into the eyes, it is recommended to rinse the eyes with warm water.

Drug Interactions

In vitro studies have shown that neither Nepafenac nor amfenac inhibits the metabolic activity of human cytochrome P450 (isoenzymes CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) at concentrations up to 3000 ng/mL. Therefore, interaction involving cytochrome P450 isoenzymes during concomitant use with other drugs is unlikely. Interaction mediated by plasma protein binding is also unlikely.

Data on the concomitant use of Nevanac^® and prostaglandin analogs are absent. Given their mechanisms of action, concomitant use is not recommended. Concomitant use of topical NSAIDs and topical steroids may increase the likelihood of healing problems. Concomitant use of Nevanac^® with drugs that prolong bleeding time may increase the risk of bleeding (see the “Special Precautions” section).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years.

After opening the bottle, the drug should be used within 28 days.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.