NEVANAC 1 mg/ml eye drops, suspension

1 ml of suspension contains 1 mg nepafenac.

Excipients: benzalkonium chloride 0.05 mg.

For a full list of excipients, see section 6.1.

Eye drops, suspension (eye drops)

Light yellow to light orange uniform suspension, pH 7.4 (approximately).

Nevanac is indicated for:

- Prevention and treatment of postoperative pain and inflammation associated with cataract surgery

- Reduction in the risk of postoperative macular oedema associated with cataract surgery in diabetic patients.

(see section 5.1)

Use in adults, including the elderly

For the prevention and treatment of pain and inflammation, the dose is 1 drop of NEVANAC in the conjunctival sac of the affected eye(s) 3 times daily beginning 1 day prior to cataract surgery, continued on the day of surgery and up to 21 days 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 oedema associated with cataract surgery in diabetic patients, the dose is 1 drop of NEVANAC in the conjunctival sac of the affected eye(s) 3 times 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.

Paediatric population

The safety and efficacy of NEVANAC in children has not been established. No data are available. There is no relevant use of NEVANAC in the paediatric population in the indications.

Use in hepatic and renal impairment

NEVANAC 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.

Method of administration

For ocular use.

Instruct patients to shake the bottle well before use.

If more than one topical ophthalmic medicinal product is being used, the medicines must be administered at least 5 minutes apart.

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. Instruct patients to keep the bottle tightly closed when not in use.

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

Like other NSAIDs, NEVANAC is also contraindicated in patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other NSAIDs.

Do not inject. Instruct patients not to swallow NEVANAC.

Instruct patients to avoid sunlight during treatment with NEVANAC.

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. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of NEVANAC 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 may increase the potential for healing problems.

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 patient risk for occurrence and severity of corneal adverse reactions.

There have been reports that ophthalmic NSAIDs may cause increased bleeding of ocular tissues (including hyphaemas) in conjunction with ocular surgery. Use NEVANAC with caution in patients with known bleeding tendencies or who are receiving other medicinal products which may prolong bleeding time.

There are very limited data on the concomitant use of prostaglandin analogues and NEVANAC. Considering their mechanisms of action, the concomitant use of these medicinal products is not recommended.

NEVANAC contains benzalkonium chloride which may cause irritation and is known to discolour soft contact lenses. Additionally, contact lens wear is not recommended during the postoperative period following cataract surgery. Therefore, patients should be advised not to wear contact lenses during treatment with NEVANAC.

Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since NEVANAC contains benzalkonium chloride, close monitoring is required with frequent or prolonged use.

An acute ocular infection may be masked by the topical use of anti-inflammatory medicines. NSAIDs do not have any antimicrobial properties. In case of ocular infection, their use with anti-infectives should be undertaken with care.

Cross-sensitivity

There is a potential for cross-sensitivity of nepafenac to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs.

In vitro studies have demonstrated a very low potential for interaction with other medicinal products and protein binding interactions (see section 5.2).

Fertility

There are no data on the effect of Nevanac on human fertility.

Pregnancy

There are no adequate data regarding the use of nepafenac in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Since the systemic exposure in non-pregnant women is negligible after treatment with NEVANAC, the risk during pregnancy could be considered low. Nevertheless, as inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonal/foetal development and/or parturition and/or postnatal development, NEVANAC is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breastfeeding

It is unknown whether nepafenac is excreted in human milk. Animal studies have shown 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. NEVANAC can be used during lactation.

As with any eye drops, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery.

Summary of the safety profile

In clinical studies involving over 800 patients receiving NEVANAC, approximately 3% of patients experienced adverse reactions. These events led to discontinuation in 0.6% of patients, which was less than placebo-treated patients (1.3%) in these same studies. No serious adverse events related to NEVANAC were reported in these studies.

Tabulated summary of adverse reactions

The following undesirable effects were assessed to be treatment-related and are 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, undesirable effects are presented in order of decreasing seriousness. The adverse reactions were obtained from clinical trials and postmarketing reports.

Diabetic Patients

A limited number of diabetic patients (N = 126), in a single study, were exposed to NEVANAC treatment for 60 days or greater for the prevention of macular oedema post cataract surgery. Approximately 2% of these patients experienced adverse drug reactions and these events led to discontinuation in 0.8% of patients which was the same rate as the placebo (0.8%). No serious adverse events related to NEVANAC were reported in this study.

The following undesirable effects from this study were assessed to be treatment-related and are 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), or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Description of selected adverse events

Clinical trial experience for the long-term use of NEVANAC for the prevention of macular oedema post cataract surgery in diabetic patients is limited. Ocular adverse reactions in diabetic patients may occur at a higher frequency than observed in the general population (see Section 4.4).

Patients with evidence of corneal epithelial breakdown should immediately discontinue use of NEVANAC and should be monitored closely for corneal health (see section 4.4).

From post-marketing experience with NEVANAC, cases reporting corneal epithelium defect/disorder have been identified. Severity of these cases vary 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 (eg, 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. When nepafenac is prescribed to a diabetic patient post cataract surgery to prevent macular oedema, the existence of any additional risk factor should lead to reassessment of the foreseen benefit/risk and to intensified patient monitoring.

Paediatric population

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

There is no experience of overdose with ocular use. The application of more than one drop per eye is unlikely to lead to unwanted side-effects. There is practically no risk of adverse effects due to accidental oral ingestion.

Pharmacotherapeutic group: Antiinflammatory agents, non-steroids, ATC code: S01BC10

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 NEVANAC eye drops have no significant effect on intraocular pressure.

Clinical Effects

Prevention and treatment of postoperative pain and inflammation associated with cataract surgery.

Three pivotal studies were conducted to assess the efficacy and safety of NEVANAC dosed 3 times daily as compared to vehicle and/or ketorolac trometamol in the prevention and treatment of postoperative pain and inflammation in patients undergoing cataract surgery. In these studies, study medication was initiated the day prior to surgery, continued on the day of surgery and for up to 2-4 weeks of the postoperative period. Additionally, nearly all patients received prophylactic treatment with antibiotics, according to clinical practice at each of the clinical trial sites.

In two double-masked, randomised vehicle-controlled studies, patients treated with NEVANAC had significantly less inflammation (aqueous cells and flare) from the early postoperative period through the end of treatment than those treated with vehicle.

In one double-masked, randomised, vehicleand active-controlled study, patients treated with NEVANAC had significantly less inflammation than those treated with vehicle. Additionally, NEVANAC was non-inferior to ketorolac 5 mg/ml in reducing inflammation and ocular pain, and was slightly more comfortable upon instillation.

A significantly higher percentage of patients in the NEVANAC group reported no ocular pain following cataract surgery compared to those in the vehicle group.

Reduction in the risk of postoperative macular oedema associated with cataract surgery in diabetic patients.Three studies (one in diabetic patients and two in non-diabetic patients) were conducted to assess the efficacy and safety of NEVANAC for the prevention of postoperative macular oedema associated with cataract surgery. In these studies, study medication was initiated the day prior to surgery, continued on the day of surgery and for up to 90 days of the postoperative period.

In 1 double-masked, randomised vehicle-controlled study, conducted in diabetic retinopathy patients, a significantly greater percentage of patients in the vehicle group developed macular oedema (16.7%) compared to patients treated with NEVANAC (3.2%). A greater percentage of patients treated with vehicle experienced a decrease in BCVA of more than 5 letters from day 7 to day 90 (or early exit) (11.5%) compared with patients treated with Nepafenac (5.6%). More patients treated with NEVANAC achieved a 15 letter improvement in BCVA compared to vehicle patients, 56.8% compared to 41.9%. respectively, p=0.019.

Absorption

Following 3 times daily dosing of NEVANAC eye drops in both eyes, 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 were 0.310 ± 0.104 ng/ml and 0.422 ± 0.121 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 radioactive labelled 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 300 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 faecal excretion represented approximately 6% of the dose. Nepafenac and amfenac were not quantifiable in the urine.

Following a single dose of NEVANAC in 25 cataract surgery patients, aqueous humour concentrations were measured at 15, 30, 45 and 60 minutes post-dose. The maximum mean aqueous humour concentrations were observed at the 1 hour time-point (nepafenac 177 ng/ml, amfenac 44.8 ng/ml). These findings indicate rapid corneal penetration.

Non-clinical data reveal no special hazard for humans based upon 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 postimplantation loss, reduced foetal weights and growth, and reduced foetal 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.

Mannitol (E421)

Carbomer

Sodium chloride

Tyloxapol

Disodium edetate

Benzalkonium chloride

Sodium hydroxide and/or hydrochloric acid (for pH adjustment)

Purified water

Not applicable.

2 years.

Discard 4 weeks after first opening.

Do not store above 30°C.

5 ml round low density polyethylene bottle with a dispensing plug and white polypropylene screw cap containing 5 ml suspension.

Carton containing 1 bottle.

No special requirements.

Alcon Laboratories (UK) Ltd.

Boundary Way

Hemel Hempstead

Herts HP2 7UD

United Kingdom

EU/1/07/433/001

Date of first authorisation: 11/12/07

22 Dec 2011