NEVANAC 1mg / ml ophthalmic drops suspension medication leaflet

NEVANAC 1 mg/ml eye drops, suspension

1 ml of suspension contains 1 mg nepafenac.

Each ml of suspension contains 0.05 mg of benzalkonium chloride.

For the full list of excipients, see section 6.1.

Eye drops, suspension

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

NEVANAC 1 mg/ml is indicated in adults for:

- Prevention and treatment of postoperative pain and inflammation associated with cataractsurgery

- Reduction in the risk of postoperative macular oedema associated with cataract surgery indiabetic patients (see section 5.1)

Adults, including the elderly

For the prevention and treatment of pain and inflammation, the dose is 1 drop of NEVANAC in theconjunctival sac of the affected eye(s) 3 times daily 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 beextended to the first 3 weeks of the postoperative period as directed by the clinician. An additionaldrop should be administered 30 to 120 minutes prior to surgery.

For the reduction in the risk of postoperative macular oedema associated with cataract surgery indiabetic 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 to60 days of the postoperative period as directed by the clinician. An additional drop should beadministered 30 to 120 minutes prior to surgery.

NEVANAC has not been studied in patients with hepatic disease or renal impairment. Nepafenac iseliminated primarily through biotransformation and the systemic exposure is very low followingtopical ocular administration. No dose adjustment is warranted in these patients.

The safety and efficacy of NEVANAC in children and adolescents have not been established. No dataare 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 youngerpatients.

For ocular use.

Patients should be instructed to shake the bottle well before use. After cap is removed, if tamperevident snap collar is loose, remove before using product.

If more than one topical ophthalmic medicinal product is being used, the medicinal product must beadministered 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. Patients should be instructed tokeep the bottle tightly closed when not in use.

If a dose is missed, a single drop should be applied as soon as possible before reverting to regularroutine. Do not use a double dose to make up for the 1 missed.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to other nonsteroidal anti-inflammatory drugs (NSAIDs).

Patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acidor other NSAIDs.

The product should not be injected. Patients should be instructed not to swallow NEVANAC.

Patients should be instructed 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 orcorneal perforation (see section 4.8). These events may be sight threatening. Patients with evidence ofcorneal epithelial breakdown should immediately discontinue use of NEVANAC and should bemonitored closely for corneal health.

Topical NSAIDs may slow or delay healing. Topical corticosteroids are also known to slow or delayhealing. Concomitant use of topical NSAIDs and topical steroids may increase the potential forhealing problems. Therefore, it is recommended that caution should be exercised if NEVANAC isadministered concomitantly with corticosteroids, particularly in patients at high risk for cornealadverse reactions described below.

Post-marketing experience with topical NSAIDs suggests that patients with complicated ocularsurgeries, 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 timemay 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 increasepatient 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. NEVANAC should be used with caution inpatients with known bleeding tendencies or who are receiving other medicinal products which mayprolong bleeding time.

An acute ocular infection may be masked by the topical use of anti-inflammatory medicinal products.

NSAIDs do not have any antimicrobial properties. In case of ocular infection, their use with anti-infectives should be undertaken with care.

Contact lenses

Contact lens wear is not recommended during the postoperative period following cataract surgery.

Therefore, patients should be advised not to wear contact lenses unless clearly indicated by theirdoctor.

NEVANAC contains benzalkonium chloride which may cause eye irritation and is known to discoloursoft contact lenses. If contact lenses need to be used during treatment, patients should be advised toremove contact lenses prior to application and wait at least 15 minutes before reinsertion.

Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerativekeratopathy. Since NEVANAC contains benzalkonium chloride, close monitoring is required withfrequent or prolonged use.

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

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

Prostaglandin analogues

There are very limited data on the concomitant use of prostaglandin analogues and NEVANAC.

Considering their mechanism of action, the concomitant use of these medicinal products is notrecommended.

Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.

Concomitant use of NEVANAC with medications that prolong bleeding time may increase the risk ofhaemorrhage (see section 4.4).

NEVANAC should not be used by women of child bearing potential not using contraception.

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

It is unknown whether nepafenac is excreted in human milk. Animal studies have shown excretion ofnepafenac in the milk of rats. However, no effects on the suckling child are anticipated since thesystemic exposure of the breast-feeding woman to nepafenac is negligible. NEVANAC can be usedduring breast-feeding.

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

NEVANAC has no or negligible influence on the ability to drive and use machines.

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 orusing machines.

In clinical studies involving 2 314 patients receiving NEVANAC 1 mg/ml the most common adversereactions were punctate keratitis, foreign body sensation and eyelid margin crusting which occurred inbetween 0.4% and 0.2% of patients.

The following adverse reactions 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 the available data). Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness. The adversereactions were obtained from clinical trials and post-marketing reports.

System organ classification Adverse reactions

Immune system disorders Rare: hypersensitivity

Nervous system disorders Rare: dizziness, headache

Eye disorders Uncommon: keratitis, punctate keratitis, cornealepithelium defect, foreign body sensation in eyes,eyelid margin crusting

Rare: iritis, choroidal effusion, corneal deposits, eyepain, ocular discomfort, dry eye, blepharitis, eyeirritation, eye pruritus, eye discharge, allergicconjunctivitis, increased lacrimation, conjunctivalhyperaemia

Not known: corneal perforation, impaired healing(cornea), corneal opacity, corneal scar, reduced visualacuity, eye swelling, ulcerative keratitis, cornealthinning, blurred vision

Vascular disorders Not known: blood pressure increased

Gastrointestinal disorders Rare: nausea

Not known: vomiting

Skin and subcutaneous tissue disorders Rare: cutis laxa (dermatochalasis), allergic dermatitis

In the two clinical studies involving 209 patients, diabetic patients were exposed to NEVANACtreatment for 60 days or greater for the prevention of macular oedema post cataract surgery. The mostfrequently reported adverse reaction was punctate keratitis which occurred in 3% of patients, resultingin a frequency category of common. The other reported adverse reactions were corneal epitheliumdefect and allergic dermatitis which occurred in 1% and 0.5% of patients, respectively both adversereactions with a frequency category of uncommon.

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

Patients with evidence of corneal epithelial breakdown including corneal perforation shouldimmediately discontinue use of NEVANAC and should be monitored closely for corneal health (seesection 4.4).

From post-marketing experience with NEVANAC, cases reporting corneal epithelium defect/disorderhave been identified. Severity of these cases vary from non serious effects on the epithelial integrity ofthe corneal epithelium to more serious events where surgical interventions and/or medical therapy arerequired to regain clear vision.

Post-marketing experience with topical NSAIDs suggests that patients with complicated ocularsurgeries, 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 beat increased risk for corneal adverse reactions which may become sight threatening. When nepafenacis prescribed to a diabetic patient post cataract surgery to prevent macular oedema, the existence ofany additional risk factor should lead to reassessment of the foreseen benefit/risk and to intensifiedpatient monitoring.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Opthalmologicals, Anti-inflammatory agents, non-steroids, ATC code:

S01BC10

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, anonsteroidal 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 withsuppression of PGE2 synthesis. Ex vivo, a single topical ocular dose of nepafenac was shown to inhibitprostaglandin synthesis in the iris/ciliary body (85%-95%) and the retina/choroid (55%) for up to6 hours and 4 hours, respectively.

The majority of hydrolytic conversion is in the retina/choroid followed by the iris/ciliary body andcornea, consistent with the degree of vascularised tissue.

Results from clinical studies indicate that NEVANAC eye drops have no significant effect onintraocular pressure.

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 timesdaily as compared to vehicle and/or ketorolac trometamol in the prevention and treatment ofpostoperative pain and inflammation in patients undergoing cataract surgery. In these studies, studymedication was initiated the day prior to surgery, continued on the day of surgery and for up to2-4 weeks of the postoperative period. Additionally, nearly all patients received prophylactic treatmentwith antibiotics, according to clinical practice at each of the clinical trial sites.

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

In one double-masked, randomised, vehicle and 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 wasslightly more comfortable upon instillation.

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

Reduction in the risk of postoperative macular oedema associated with cataract surgery in diabeticpatients

Four studies (two in diabetic patients and two in non-diabetic patients) were conducted to assess theefficacy and safety of NEVANAC for the prevention of postoperative macular oedema associated withcataract surgery. In these studies, study medication was initiated the day prior to surgery, continued onthe 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, asignificantly 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 withvehicle 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.

The European Medicines Agency has waived the obligation to submit the results of studies with

NEVANAC in all subsets of the paediatric population in prevention and treatment of post operativepain and inflammation associated with cataract surgery and prevention of post surgical macularoedema (see section 4.2 for information on paediatric use).

Following 3 times daily dosing of NEVANAC eye drops in both eyes, low but quantifiable plasmaconcentrations of nepafenac and amfenac were observed in the majority of subjects 2 and 3 hourspost-dose, respectively. The mean steady-state plasma Cmax for nepafenac and for amfenac were0.310 ± 0.104 ng/ml and 0.422 ± 0.121 ng/ml, respectively, following ocular administration.

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 distributewidely in the body following single and multiple oral doses of 14C-nepafenac.

Studies in rabbits demonstrated that the topically administered nepafenac is distributed locally fromthe front of the eye to the posterior segments of the eye (retina and choroid).

Nepafenac undergoes relatively rapid bioactivation to amfenac via intraocular hydrolases.

Subsequently, amfenac undergoes extensive metabolism to more polar metabolites involvinghydroxylation of the aromatic ring leading to glucuronide conjugate formation. Radiochromatographicanalyses before and after β-glucuronidase hydrolysis indicated that all metabolites were in the form ofglucuronide conjugates, with the exception of amfenac. Amfenac was the major metabolite in plasma,representing approximately 13% of total plasma radioactivity. The second most abundant plasmametabolite was identified as 5-hydroxy nepafenac, representing approximately 9% of totalradioactivity at Cmax.

Interactions with other medicinal products: Neither nepafenac nor amfenac inhibit any of the majorhuman cytochrome P450 (CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) metabolic activities in vitro atconcentrations up to 3 000 ng/ml. Therefore, interactions involving CYP-mediated metabolism ofconcomitantly administered medicinal products are unlikely. Interactions mediated by protein bindingare also unlikely.

After oral administration of 14C-nepafenac to healthy volunteers, urinary excretion was found to be themajor route of radioactive excretions, accounting for approximately 85% while faecal excretionrepresented 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 concentrationswere measured at 15, 30, 45 and 60 minutes post-dose. The maximum mean aqueous humourconcentrations 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 on conventional studies of safetypharmacology, 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 wereassociated with dystocia, increased postimplantation loss, reduced foetal weights and growth, andreduced foetal survival. In pregnant rabbits, a maternal dose of 30 mg/kg that produced slight toxicityin the mothers showed a statistically significant increase in the incidence of litter malformations.

Mannitol (E421)

Carbomer

Sodium chloride

Tyloxapol

Disodium edetate

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.

For storage conditions after first opening of the medicinal product, see section 6.3.

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

Carton containing 1 bottle.

No special requirements for disposal.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/07/433/001

Date of first authorisation: 11 December 2007

Date of latest renewal: 24 September 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu