Drug Interactions
Interactions with herbal products are not anticipated following topical ocular administration.
Interactions with food are not anticipated following topical ocular administration.
NEVANAC (nepafenac) Ophthalmic Suspension may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics.
The administration of NEVANAC Suspension in conjunction with prostaglandin analogues was not evaluated in clinical trials. Interactions between NEVANAC Suspension and prostaglandin analogues are not anticipated following topical ocular administration.
There is a potential cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents.
Interactions with laboratory tests are not anticipated following topical ocular administration.
Neither nepafenac nor amfenac inhibits any of the major human cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) metabolic activities in vitro at concentrations up to 300 ng/mL. Therefore, drug-drug interactions involving CYP-mediated metabolism of concomitantly administered drugs are unlikely. Drug-drug interactions mediated by protein binding are also unlikely.
Information for the Patient
Nevanac
Special Handling Instructions
None.
Dosage and Administration
NEVANAC (nepafenac) Ophthalmic Suspension 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.
Shake well before use. One drop of NEVANAC Suspension should be applied to the affected eye(s) three-times-daily beginning 1 day prior to cataract surgery, and continued on the day of surgery and through the first 2 weeks of the postoperative period.
NEVANAC Suspension has been safely administered in conjunction with other ophthalmic medications such as antibiotics, anesthetics, beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics. Because the administration of NEVANAC Suspension in conjunction with prostaglandin analogues has not been studied, use only if the benefit outweighs any potential risk.
If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart.
Contact lens wear is not recommended during the postoperative period following cataract surgery; therefore, contact lenses should not be worn during treatment with NEVANAC Suspension.
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 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 regular routine. Do not use a double dose to make up for the one missed.
Adverse Reactions
allergic conjunctivitis, choroidal effusion, conjunctival hyperaemia, corneal deposits, eye discharge, eye irritation, eyelid disorder, iritis, keratitis, ocular discomfort, photophobia.
Adverse reactions identified from postmarketing experience that have not been reported previously in clinical trials with NEVANAC Suspension include the following: ulcerative keratitis, corneal epithelium defect/disorder, corneal abrasion, anterior chamber inflammation, impaired healing (cornea), reduced visual acuity, corneal scar, corneal opacity.
NEVANAC Suspension had no clinically relevant effect on laboratory parameters.
MedDRA Preferred Term
(Version 9.0) | NEVANAC
0.1%
n=811
(%) | Placebo
n=529
(%) | Ketorolac
0.5%
n=73
(%) | Ketorolac
0.4%
n=163
(%) | Diclofenac
0.1%
n=44
(%) |
| Eye Disorders |
| Eyelid margin crusting | 0.6 | | 1.4 | | |
| Eye pain | 0.5 | 0.9 | | 2.5 | |
| Punctate keratitis | 0.5 | 0.6 | 1.4 | | |
| Vision blurred | 0.5 | 0.2 | | | |
| Foreign body sensation | 0.4 | 1.5 | | | |
| Dry eye | 0.4 | 0.2 | | | |
| Eye pruritus | 0.4 | | | | |
| Lacrimation increased | 0.2 | 0.2 | | | |
| Nervous System Disorders |
| Headache | 0.4 | | | | |
In clinical studies with over 800 patients receiving NEVANAC (nepafenac) Ophthalmic Suspension, 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 Suspension were reported in these studies.
Indications and Clinical Use
The safety and effectiveness of NEVANAC Suspension in pediatric patients have not been established. Its use is not recommended in these patients until further data become available.
No overall differences in safety and effectiveness have been observed between elderly and younger patients.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
A topical overdosage may be flushed from the eye(s) with warm tap water.
There is minimal risk of adverse effects due to accidental ingestion of a 5 mL bottle of NEVANAC (nepafenac) Ophthalmic Suspension (total dose of 5 mg) by a child. The recommended adult dose of amfenac sodium (FENAZOX), marketed in Japan since 1986, is one to four 50 mg tablets daily. This translates to 1 to 4 mg/kg per day for a 50 kg person. If a 20 kg child ingested the entire contents of a 5 mL bottle of NEVANAC Suspension, it would translate to a dose of 0.25 mg/kg or only 6% to 25% of the recommended adult dose.
Dosage Forms, Composition and Packaging
Each mL of ophthalmic suspension contains: nepafenac 1 mg (0.1%). Nonmedicinal ingredients: benzalkonium chloride as a preservative 0.005%, carbomer 974P, edetate disodium, mannitol, purified water, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH) and tyloxapol. Round low density polyethylene bottles of 8 mL with a natural low density polyethylene dispensing plug and white polypropylene cap. Tamper evidence is provided by a closure with an extended skirt that locks to the bottle finish on application and breaks away from the closure on opening. Net contents are 5 mL supplied in an 8 mL bottle.
Warnings and Precautions
No overall differences in safety and effectiveness have been observed between elderly and younger patients.
With some NSAIDs, including NEVANAC Suspension, the potential exists for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ophthalmic NSAIDs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.
It is recommended that NEVANAC Suspension be used with caution in patients with known bleeding tendencies or who are receiving medications which may prolong bleeding time.
There is a potential for cross-sensitivity of nepafenac to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.
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.
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 Suspension and should be closely monitored for corneal health.
Postmarketing 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 events which may become sight-threatening. Topical NSAIDs should be used with caution in these patients. Postmarketing experience also suggests that prolonged use of topical NSAIDs may increase patient risk for occurrence and severity of corneal adverse reactions.
Contact lens wear is not recommended during the postoperative period following cataract surgery; therefore, contact lenses should not be worn during treatment with NEVANAC Suspension.
Nepafenac did not impair fertility when administered orally to male and female rats at 3 mg/kg (approximately 90 and 380 times the plasma exposure to the parent drug, nepafenac, and the active metabolite, amfenac, respectively, at the recommended human topical ophthalmic dose).
No adequate and well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, NEVANAC Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because of the known effects of prostaglandin biosynthesis inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of NEVANAC Suspension during late pregnancy should be avoided.
Reproduction studies performed with nepafenac in rabbits and rats at oral doses up to 10 mg/kg/day have revealed no evidence of teratogenicity due to nepafenac, despite the induction of maternal toxicity. At this dose, the animal plasma exposure to nepafenac and amfenac was approximately 260 and 2400 times human plasma exposure at the recommended human topical ophthalmic dose for rats and 80 and 680 times human plasma exposure for rabbits, respectively. In rats, maternally toxic doses ≥10 mg/kg were associated with dystocia, increased postimplantation loss, reduced fetal weights and growth, and reduced fetal survival. Nepafenac has been shown to cross the placental barrier in rats.
The safety and effectiveness of NEVANAC Suspension in pediatric patients have not been established. Its use is not recommended in these patients until further data become available.
It is unknown whether nepafenac is excreted in human milk. Animal studies have shown excretion of nepafenac in the milk of pregnant rats. Caution should be exercised when NEVANAC Suspension is administered to a nursing woman.
Storage and Stability
Store at 2-30°C. Discard 28 days after opening.
Action and Clinical Pharmacology
No overall differences in safety and effectiveness have been observed between elderly and younger patients.
Amfenac has high affinity toward serum albumin proteins. In vitro, the percent bound to human albumin and human serum was 95.4% and 99.1%, respectively.
Studies in rats have shown that radioactive drug-related materials distribute widely in the body following single and multiple oral doses of 14C-nepafenac.
| | Cmax
(ng/mL) | Tmax
(h) | AUC0-8
(ng·h/mL) | t½
(h) |
| Nepafenac | 0.310±0.104 | 0.25±0.10 | 0.368±0.106 | 0.9±0.2 |
| Amfenac | 0.422±0.121 | 0.55±0.14 | 0.976±0.284 | 1.6±0.3 |
Following bilateral topical ocular three-times-daily dosing of NEVANAC Suspension, low but quantifiable plasma drug concentrations were observed in the majority of subjects at 2 hours (nepafenac) and 5 hours (amfenac) post-dose. 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.
Nepafenac is a nonsteroidal 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.
A comparison of the single- and steady-state pharmacokinetic data for nepafenac and amfenac in healthy Japanese and non-Japanese subjects indicate that there are no clinically meaningful ethnic differences in the systemic exposure of either nepafenac or amfenac following topical ocular administration of NEVANAC Suspension.
After oral administration of 14C-nepafenac to healthy volunteers, urinary excretion was found to be the major route of radioactivity elimination, accounting for approximately 85% of the dose while fecal excretion represented approximately 6% of the dose. Nepafenac and amfenac were not quantifiable in the urine.
Gender differences in the plasma pharmacokinetics of nepafenac and amfenac were small and not clinically relevant.
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 Cmax.
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. Topical nepafenac inhibits choroidal neovascularisation and ischemia induced retinal neovascularisation. A decreased production of vascular endothelial growth factor was noted in these studies.
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. The enhanced permeability of nepafenac, combined with rapid bioactivation, make it a target-specific NSAID for inhibiting prostaglandin formation in the anterior and posterior segments of the eye.
Results from clinical studies indicate the NEVANAC (nepafenac) Ophthalmic Suspension has no significant effect on intraocular pressure.
NEVANAC Suspension has not been studied in patients with hepatic disease or renal impairment. The systemic exposure is very low following topical ocular administration and no dose adjustment is warranted in these patients.
NEVANAC Suspension has not been evaluated in the pediatric population.
Contraindications
NEVANAC (nepafenac) Ophthalmic Suspension is contraindicated in patients who are hypersensitive to nepafenac, to any ingredient in the formulation or component of the container (for a complete listing see the Dosage Forms, Composition and Packaging), or to other nonsteroidal anti-inflammatory drugs (NSAIDs).
