NEVANAC® Eye drops, suspension
SCHEDULING STATUS
S3
PROPRIETARY NAME
(and dosage form)
NEVANAC® Eye drops, suspension
COMPOSITION
1 mL of suspension contains 1 mg nepafenac.
Preservatives: benzalkonium chloride 0.005% (m/v) and disodium edetate 0.01% (m/v).
PHARMACOLOGICAL CLASSIFICATION
A.15.4 Ophthalmic preparations, Anti-inflammatory agents, non-steroids
ATC code: S01BC10
PHARMACOLOGICAL ACTION
Pharmacodynamic properties
Mechanisms 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 non-steroidal anti-inflammatory drug. Amfenac inhibits the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.
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.
Pharmacokinetic properties
Absorption
Following three-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 Cmax 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, 98,4%, 95,4% and 99,1% was bound to rat albumin, human albumin and human serum, respectively.
Metabolism
Nepafenac undergoes 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 beta-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 Cmax.
Excretion/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 nepafenac 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.
INDICATIONS
Prevention and treatment of pain and inflammation associated with cataract surgery.
CONTRA-INDICATIONS
Hypersensitivity to the active substance, to any of the excipients, or to other non-steroidal anti-inflammatory drugs (NSAIDs).
Cardiovascular: Heart failure.
Gastrointestinal: History of gastrointestinal bleeding or perforation (PUB’s) related to previous NSAIDs. Active or history of recurrent ulcer/haemorrhage/perforations.
NEVANAC is also contra-indicated in patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or other NSAIDs.
WARNINGS
Special warning and precautions for use
Use of topical NEVANAC may result in keratitis. Continued use of topical NEVANAC 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 NEVANAC may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of NEVANAC 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. NEVANAC should be used with caution in these patients. Prolonged use of NEVANAC may increase patient risk for occurrence and severity of corneal adverse reactions.
Ophthalmic NSAIDs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery. Use NEVANAC with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.
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 antimicrobial properties. In case of ocular infection, they should be used with care with anti-infectives.
Cardiovascular: Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NEVANAC therapy.
Gastrointestinal:Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation (PUBs) which may be fatal. The risk of gastrointestinal bleeding or perforation is higher with increasing doses of NEVANAC, in patients with a history of ulcers and the elderly. When gastrointestinal bleeding or ulceration occurs in patients receiving NEVANAC, treatment with NEVANAC should be stopped. NEVANAC should be given with caution to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohn’s disease, hiatus hernia, gastro-oesophageal reflux disease, angiodysplasia) as the condition may be exacerbated.
Skin Reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. NEVANAC should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Cross-sensitivity
There is a potential for cross-sensitivity of NEVANAC to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs.
INTERACTIONS
Interactions with other medicines: 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, drug-drug interactions involving CYP-mediated metabolism of concomitantly administered medicines are unlikely.
In vitro studies have demonstrated a very low potential for drug-drug and protein binding interactions. Interactions mediated by protein binding are also unlikely.
Use of two or more NSAIDs concomitantly could result in an increase in side effects.
Gastrointestinal
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (PUBs).
Anti-coagulants: NEVANAC may enhance the effects of anti-coagulants such as warfarin.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of intestinal bleeding.
NEVANAC eye drops may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics and mydriatics.
PREGNANCY AND LACTATION
Pregnancy
There are no adequate data from the use of NEVANAC in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. As inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonal/foetal development and/or parturition and/or postnatal development, Nevanac should not be used during pregnancy.
Regular use of non-steroidal anti-inflammatory drugs during the 3rd trimester of pregnancy, may result in premature closure of the foetal ductus arteriousus in utero and possibly in persistent pulmonary hypertension of the new-born. The onset of labour may be delayed and its duration increased.
Breast-feeding women
It is unknown whether NEVANAC is excreted in human milk. Animal studies have shown excretion of NEVANAC in the milk of lactating rats. NEVANAC should not be used during breast-feeding.
DOSAGE AND DIRECTIONS FOR USE
Use in adults, including the elderly
Use the lowest effective dose for the shortest possible duration of treatment.
Instil one drop of NEVANAC in the conjunctival sac of the affected eye(s) three 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 be extended to the first 3 weeks of the postoperative period, as directed by the clinician. An additional drop should be administered 30-120 minutes prior to surgery.
Paediatric patients
The efficacy and safety of NEVANAC in patients below the age of 18 years has not been established.
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.
For ocular use
Shake well before use.
If more than one topical ophthalmic medication 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.
Keep the bottle tightly closed when not in use.
SIDE EFFECTS AND SPECIAL PRECAUTIONS
Undesirable effects
In clinical studies involving over 800 patients receiving NEVANAC eye drops, approximately 5% of patients experienced adverse reactions. These events led to discontinuation in 0,5% 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.
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 <1/1000) or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Immune system disorders
Uncommon: hypersensitivity.
Nervous system disorders
Common: headache.
Eye disorders
Common: punctate keratitis, eye pain, blurred vision, eye pruritus, dry eye, foreign body sensation in eyes, eyelid margin crusting.
Uncommon: iritis, keratitis, corneal deposits, choroidal effusion, eye discharge, photophobia, eye irritation, allergic conjunctivitis, ocular discomfort, eyelid disorder, increased lacrimation, conjunctival hyperaemia.
Gastrointestinal disorders
Uncommon: nausea, dry mouth.
Skin and subcutaneous tissue disorders
Uncommon: cutis laxa (dermatochalasis).

Data obtained from package inserts of other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):
Cardiovascular: Oedema, hypertension and cardiac failure.
Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, malaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease, gastritis.
Skin and subcutaneous tissue disorders: Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Adverse reactions identified from post-marketing experience that have not been reported previously in clinical trials with NEVANAC include the following. The frequency category in which these adverse reactions occur is not known and cannot be estimated from the available data.
Eye disorders: ulcerative keratitis, corneal epithelium defect/disorder, corneal abrasion, anterior chamber inflammation, impaired healing (cornea), reduced visual acuity, corneal scarring, corneal opacity.

Patients with evidence of corneal epithelial breakdown should immediately discontinue use of NEVANAC and should be monitored closely for corneal health.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
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.

IDENTIFICATION
Light yellow to light orange uniform suspension.

PRESENTATION
5 mL round, colourless low density polyethylene bottle and dispensing plug with white polypropylene screw cap containing 5 mL suspension.

STORAGE INSTRUCTIONS
Keep the container well-closed after opening. Discard four weeks after first opening.
KEEP OUT OF SIGHT AND REACH OF CHILDREN.
Do not store above 30°C.

REGISTRATION NUMBER
42/15.4/1006

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Alcon Laboratories (SA) (Pty) Ltd
65 Peter Place
Bryanston Extension 13
2191
DATE OF PUBLICATION OF THE PACKAGE INSERT
15 April 2011

New addition to this site: September 2014
Source: Pharmaceutical Industry