Nevanac

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEVANAC® (NEVANAC®)

Composition:

Active substance: nepafenac;

1 ml of suspension contains 3 mg of nepafenac;

Excipients: benzalkonium chloride, sodium carmellose, guar gum, carbomer 974P, boric acid; edetate disodium dihydrate; propylene glycol, sodium chloride, sodium hydroxide and/or hydrochloric acid concentrated (for pH adjustment), purified water.

Pharmaceutical form. Eye drops.

Main physicochemical characteristics: homogeneous suspension from light yellow to dark orange in color.

Pharmacotherapeutic group. Agents used in ophthalmology. Non-steroidal anti-inflammatory agents. Nepafenac. ATC code S01BC10.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Nepafenac belongs to nonsteroidal anti-inflammatory and analgesic prodrugs. After topical ocular administration, nepafenac penetrates into the cornea and is converted to amfenac, a nonsteroidal anti-inflammatory agent, by ocular tissue hydrolases. Amfenac inhibits prostaglandin H synthase (cyclooxygenase), an enzyme essential for prostaglandin production.

Secondary Pharmacology

In animal studies, nepafenac was shown to reduce the permeability of the blood-retinal barrier while simultaneously inhibiting PGE2 (prostaglandin E2) synthesis in rabbits. Under ex vivo conditions, a single topical ocular dose of nepafenac was confirmed to inhibit 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 conversion occurs in the retina/choroid, followed by the iris/ciliary body and cornea, depending on the degree of tissue vascularization.

Clinical study results indicate that Nevanac® ophthalmic suspension, 3 mg/mL, has 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 Nevanac®, ophthalmic suspension, 3 mg/mL, for the prevention and treatment of postoperative pain and inflammation in patients undergoing cataract surgery were demonstrated in two double-blind, randomized, placebo-controlled studies involving 1339 patients.

Treatment with the study drug was initiated one day before surgery, continued on the day of surgery, and maintained for the first 14 days of the postoperative period. Nevanac®, ophthalmic suspension, 3 mg/mL, demonstrated superior clinical efficacy compared to placebo in the treatment of postoperative pain and inflammation.

Results from two double-blind, randomized, placebo-controlled studies showed significantly less inflammation (aqueous flare and cells) in patients treated with Nevanac® during the early postoperative period and through the end of treatment compared to those receiving placebo. In both studies, inflammation resolved by day 14 post-surgery in 65% and 68% of patients treated with Nevanac® versus 25% and 35% of those receiving placebo.

Pain resolution rates in the Nevanac® group were 89% and 91% compared to 40% and 50% in the placebo group.

Some patients received Nevanac®, ophthalmic suspension, 3 mg/mL, for up to 21 days post-surgery. However, efficacy beyond 14 days post-surgery was not established.

Additionally, in one of the two clinical trials, Nevanac® ophthalmic suspension, 3 mg/mL, administered once daily, was non-inferior to Nevanac® ophthalmic suspension, 1 mg/mL, administered three times daily, in the prevention and treatment of postoperative pain and inflammation following cataract surgery.

Resolution of inflammation and pain relief were comparable between both formulations at all postoperative assessments.

Reduction of the risk of postoperative macular edema associated with cataract surgery in patients with diabetes mellitus.

Two studies were conducted to evaluate the efficacy and safety of Nevanac®, 3 mg/mL suspension, administered once daily, for the prevention of macular edema following cataract surgery. The drug was administered one day before surgery, on the day of surgery, and throughout the postoperative period lasting up to 90 days.

In two double-blind, randomized, placebo-controlled studies involving patients with diabetic retinopathy, macular edema occurred significantly more frequently in the placebo group (17.3% and 14.3%) compared to the group treated with Nevanac®, ophthalmic suspension, 3 mg/mL (2.3% and 5.9%). Integrated analysis of the two studies showed macular edema rates of 15.9% in the placebo group and 4.1% in the Nevanac® group (p < 0.001). In most patients treated with Nevanac®, improvement in best-corrected visual acuity by 15 letters was achieved by day 14. This improvement was maintained through day 90 in the Nevanac® ophthalmic suspension, 3 mg/mL group (61.7%) compared to the placebo group (43%) in one study; the percentage of patients was similar between the two treatment groups for this endpoint in the second study (48.8% in the Nevanac® group and 50.5% in the placebo group). In the integrated analysis of both studies, the percentage of subjects achieving a 15-letter improvement in visual acuity by day 14 and maintaining improvement through day 90 was higher in the Nevanac®, ophthalmic suspension, 3 mg/mL group (55.4%) compared to the placebo group (46.7%, p = 0.003).

Preclinical Safety Data

Preclinical data revealed no special risk to humans based on standard safety pharmacology, repeated-dose toxicity, and genotoxicity studies.

Long-term carcinogenicity studies with nepafenac have not been conducted.

In reproductive toxicity studies in rats, maternal toxicity at doses ≥10 mg/kg was associated with dystocia, increased post-implantation loss, reduced fetal body weight, delayed embryonic development, and decreased fetal survival. In pregnant rabbits, administration of a dose of 30 mg/kg, which caused minimal maternal toxicity, resulted in a statistically significant increase in fetal malformations.

Pharmacokinetics

Absorption

After instillation of Nevanac® ophthalmic suspension, 3 mg/mL, into both eyes once daily, plasma concentrations of nepafenac and amfenac in most patients were low but quantifiable at 2 and 3 hours post-dose, respectively. The mean steady-state plasma concentration (C_max) of nepafenac and amfenac following topical administration was 0.847 ± 0.269 ng/mL and 1.13 ± 0.491 ng/mL, respectively.

Distribution

Amfenac has 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.

Studies in rats showed that after single or multiple oral doses of 14C-nepafenac, radioactivity associated with the active drug substance distributed throughout the body.

Studies in rabbits demonstrated that topically administered nepafenac spreads locally from the anterior segment of the eye to the posterior segments (retina and choroid).

Biotransformation

Nepafenac is rapidly bioactivated to amfenac by intraocular hydrolases. Amfenac is then extensively metabolized to more polar metabolites, including aromatic ring hydroxylation, leading to glucuronide conjugation. Radiochromatographic analysis before and after β-glucuronidase hydrolysis showed that all metabolites except amfenac were present as glucuronide conjugates. Amfenac was the predominant compound in plasma, accounting for approximately 13% of total plasma radioactivity. The second major metabolite in plasma was 5-hydroxynepafenac, representing approximately 9% of total radioactivity at C_max.

Interaction with other medicinal products: In vitro, nepafenac and amfenac do not inhibit the metabolism of major cytochrome P450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) in humans at concentrations up to 3000 ng/mL. Therefore, drug interactions mediated by CYP-dependent metabolism of concomitantly administered drugs are unlikely. Protein binding-mediated interactions are also unlikely.

Elimination

After oral administration of 14C-nepafenac to healthy volunteers, the compound was primarily excreted in urine (approximately 85%), with only about 6% eliminated via feces.

Clinical characteristics.

Indications.

Nevanac® is indicated in adults for:

• prevention and treatment of pain and inflammation following cataract surgery;
• reduction of the risk of developing macular edema after cataract surgery in patients with diabetes mellitus (see section "Pharmacological properties").

Contraindications.

Hypersensitivity to the active substance, to any of the excipients, or to other nonsteroidal anti-inflammatory drugs (NSAIDs).

Nevanac® is contraindicated in patients in whom administration of acetylsalicylic acid or other NSAIDs induces asthma attacks, urticaria, or acute rhinitis.

Interaction with other medicinal products and other forms of interaction.

In vitro studies have demonstrated a low likelihood of interaction with other medicinal products and plasma protein binding.

Prostaglandin analogs.

There are very limited data regarding concomitant use of prostaglandin analogs and Nevanaс®. Due to their mechanism of action, concomitant use of these medicinal products is not recommended.

Concomitant use of topical NSAIDs and corticosteroids may impair wound healing. Concomitant use of Nevanac® with medicinal products that prolong bleeding time increases the risk of bleeding.

Special precautions for use.

Do not use for injections. Patients should be informed that the Nevanac medication must not be swallowed.

Patients should be advised to avoid exposure to sunlight during treatment with Nevanac®.

Visual effects

NSAIDs for topical use may cause keratitis. In some patients with increased sensitivity, prolonged use of topical NSAIDs may lead to epithelial damage, corneal thinning, corneal erosion, ulceration, or corneal perforation. These conditions may threaten vision loss. Patients who develop signs of corneal epithelial damage should immediately discontinue Nevanac® and undergo corneal examination.

Topical use of NSAIDs may delay or impair wound healing. It is known that topical corticosteroids also delay or impair wound healing. Concurrent use of topical NSAIDs and corticosteroids may further complicate wound healing. Therefore, caution is recommended when Nevanac® is used concomitantly with corticosteroids, especially in patients at high risk of corneal adverse reactions, as described below.

Post-marketing experience with topical NSAIDs has shown that patients undergoing complex ophthalmic surgeries, patients with corneal denervation, patients with corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeated ophthalmic surgeries within a short period may have an increased risk of corneal adverse reactions that threaten vision loss. Topical NSAIDs should be used with particular caution in such patients. Prolonged use of topical NSAIDs may increase the risk and severity of corneal adverse reactions.

There have been reports that concomitant use of NSAIDs in ophthalmology and performance of ophthalmic surgery may lead to increased bleeding in ocular tissues (including hyphema). Nevanac® should be used with caution in patients with known bleeding tendencies or those taking other medicinal products that may prolong bleeding time.

Topical use of anti-inflammatory agents may mask the development of acute ocular infection. NSAIDs have no antimicrobial properties. In case of ocular infection, NSAIDs should be used with particular caution when administered concomitantly with antibacterial agents.

Contact lenses

Wearing contact lenses is not recommended during the postoperative period following cataract surgery. Therefore, patients should be advised not to wear contact lenses unless specifically instructed by their physician.

Benzalkonium chloride

Nevanac® contains benzalkonium chloride, which may cause eye irritation and may discolor soft contact lenses. If wearing contact lenses during treatment is necessary, patients should be advised to remove contact lenses before administering the medication and wait at least 15 minutes before reinserting them.

Cases have been reported in which benzalkonium chloride caused punctate keratopathy and/or toxic ulcerative keratopathy. Since Nevanac® contains benzalkonium chloride, careful monitoring is recommended during frequent or prolonged use of the medication.

Cross-sensitivity

Cross-sensitivity between nepafenac and acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs is possible.

Use during pregnancy or breastfeeding.

Women of reproductive potential

The Nevanac® medication should not be used in women of reproductive age who are not using appropriate contraceptive methods.

Pregnancy

There are insufficient data on the use of the medication in pregnant women. Reproductive toxicity has been observed in animal studies (see section "Pharmacological properties"). The potential risk to human reproductive function is unknown. Since the systemic effect of Nevanac® in non-pregnant women is minimal, the risk of using this medication during pregnancy can be considered low. However, since inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development, and/or labor, and/or postnatal development, the use of Nevanac® during pregnancy is not recommended.

Breastfeeding

It is unknown whether nepafenac is excreted in human breast milk. Animal studies have shown that nepafenac passes into the milk of rats. However, a negative effect of the medication on the infant is not expected, since the systemic effect of nepafenac in breastfeeding women is very minimal. Therefore, Nevanac® may be used during breastfeeding.

Fertility

Data on the effect of Nevanac® on human fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

Nevanac® has no or negligible influence on the ability to drive or operate machinery.

Transient blurred vision or other visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs after instillation, patients should wait until vision clears before driving or operating machinery.

Dosage and Administration

Use in adults

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) once daily, starting 1 day before cataract surgery, then on the day of surgery and during the first 2 postoperative weeks, as directed by the physician. Treatment may be continued for the first 3 postoperative weeks at the physician's discretion. An additional drop of the medication should be administered 30–120 minutes before surgery.

To reduce the risk of postoperative macular edema after cataract surgery in patients with diabetes mellitus, instill 1 drop of Nevanac® into the conjunctival sac of the affected eye(s) once daily, starting 1 day before cataract surgery, then on the day of surgery and during the postoperative period up to 60 days, as directed by the physician. An additional drop of the medication should be administered 30–120 minutes before surgery.

The once-daily dosing regimen of Nevanac® 3 mg/mL eye drops provides the same total daily dose of nepafenac as the three-times-daily administration of Nevanac® 1 mg/mL eye drops.

Patients with hepatic or renal impairment

The use of Nevanac® in patients with hepatic or renal impairment has not been studied. Nepafenac is primarily eliminated from the body via biotransformation, and systemic effects following topical administration are minimal. Dose adjustment is not required in these patient populations.

Administration method

For ophthalmic use.

Patients should be instructed to shake the bottle well before use. After removing the cap, it is recommended to remove the plastic ring located underneath.

If multiple ophthalmic topical medications are used, an interval of at least 5 minutes between administrations is recommended. Ophthalmic ointments should be applied last.

To prevent contamination of the dropper tip and solution, avoid touching the eyelids, surrounding areas, or other surfaces with the dropper tip. The bottle should be kept tightly closed when not in use.

If a dose is missed, one drop should be administered as soon as possible before resuming the regular dosing schedule. Do not use a double dose to compensate for a missed dose.

Children

The safety and efficacy of Nevanac® in children have not been established.

Overdose

No adverse reactions are expected in case of overdose when administered into the eyes or in case of accidental ingestion.

Adverse Reactions

Overview of drug safety data

In clinical studies involving over 1900 patients using NEVANAC® ophthalmic suspension, 3 mg/mL, the most commonly reported adverse reactions were punctate keratitis, keratitis, foreign body sensation in the eye, and eye pain, occurring in between 0.4% and 0.1% of patients.

Patients with diabetes mellitus

In two clinical studies involving 594 patients with diabetes mellitus, NEVANAC® was administered for 90 days to prevent the development of macular edema following cataract surgery. The most frequently reported adverse reaction was punctate keratitis, observed in 1% of patients (frequency classification: "common"). Other most commonly reported adverse reactions were keratitis and foreign body sensation in the eye, occurring in 0.5% and 0.3% of patients, respectively (frequency classification: "uncommon").

Summary of adverse reactions

The adverse reactions listed below are classified according to frequency of occurrence as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), or not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity. Data on adverse reactions were obtained from clinical and post-marketing studies.

Specific Adverse Reactions

Patients who show signs of corneal epithelial damage, including corneal perforation, must immediately discontinue use of Nevanac® and undergo corneal evaluation (see section "Special Warnings and Precautions for Use").

Post-marketing data on the use of Nevanac® ophthalmic solution have reported cases of corneal epithelial damage/disorders. The severity of these adverse events ranges from non-serious disruption of corneal epithelial integrity to more serious events requiring surgical intervention and/or treatment to restore visual acuity.

Post-marketing experience with topical NSAIDs confirms that patients who have undergone complicated ocular surgeries, patients with corneal denervation, patients with corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeated ocular surgeries within a short period may have an increased risk of developing corneal adverse reactions that may threaten vision.

Pediatric Population

The safety and efficacy of Nevanac® in pediatric patients have not been established.

Shelf Life

18 months.

Storage period after first opening of the bottle – 4 weeks.

Storage Conditions

Store at a temperature not exceeding 25 °C. Keep the bottle in the outer cardboard package to protect from light. Store out of reach of children.

Packaging

3 ml in a dropper bottle; 1 dropper bottle in a cardboard box.

Prescription Status

Prescription only.

Manufacturer

Novartis Manufacturing NV / Novartis Manufacturing NV.

Manufacturer's Address

Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium / Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium.