HIGHLIGHTS OF PRESCRIBING INFORMATION INDICATIONS AND USAGEILEVRO™ (nepafenac ophthalmic suspension), 0.3% is a nonsteroidal, anti-inflammatory prodrug indicated for the treatment of pain and inflammation associated with cataract surgery (1).DOSAGE AND ADMINISTRATIONOne drop of ILEVRO™ (nepafenac ophthalmic suspension), 0.3% should be applied to the affected eye one-time-daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first 2 weeks of the postoperative period. An additional drop should be administered 30 to 120 minutes prior to surgery. (2) DOSAGE FORMS AND STRENGTHSSterile ophthalmic suspension 0.3%: 1.7 mL in a 4 mL bottle. (3) CONTRAINDICATIONSHypersensitivity to any of the ingredients in the formula or to other NSAIDS.(4) WARNINGS AND PRECAUTIONSIncreased bleeding time due to interference with thrombocyte aggregation (5.1)Delayed healing (5.2)Corneal effects including keratitis (5.3)Side EffectsMost common adverse reactions (5 to 10%) are capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
FULL PRESCRIBING INFORMATION: CONTENTS*
- 1 ILEVRO INDICATIONS AND USAGE SECTION
- 2 ILEVRO DOSAGE AND ADMINISTRATION SECTION
- 3 DOSAGE FORMS AND STRENGTHS SECTION
- 4 ILEVRO CONTRAINDICATIONS SECTION
- 5 WARNINGS AND PRECAUTIONS SECTION
- 6 ILEVRO ADVERSE REACTIONS SECTION
- 8 USE IN SPECIFIC POPULATIONS SECTION
- 11 ILEVRO DESCRIPTION SECTION
- 12 CLINICAL PHARMACOLOGY SECTION
- 13 NONCLINICAL TOXICOLOGY SECTION
- 14 CLINICAL STUDIES SECTION
- 16 HOW SUPPLIED/STORAGE AND HANDLING SECTION
- 17 PATIENT COUNSELING INFORMATION SECTION
- PRINCIPAL DISPLAY PANEL
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE SECTION
ILEVRO™ (nepafenac ophthalmic suspension), 0.3% is indicated for the treatment of pain and inflammation associated with cataract surgery.
2 DOSAGE AND ADMINISTRATION SECTION
2.1 Recommended Dosing
One drop of ILEVRO™ (nepafenac ophthalmic suspension), 0.3% should be applied to the affected eye one-time-daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first 2 weeks of the postoperative period. An additional drop should be administered 30 to 120 minutes prior to surgery.
2.2 Use with Other Topical Ophthalmic Medications
ILEVRO™ (nepafenac ophthalmic suspension), 0.3% may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics.
If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart.
3 DOSAGE FORMS AND STRENGTHS SECTION
Sterile ophthalmic suspension 0.3%
1.7 mL in a 4 mL bottle
4 CONTRAINDICATIONS SECTION
ILEVRO™ (nepafenac ophthalmic suspension), 0.3% is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula or to other NSAIDs.
5 WARNINGS AND PRECAUTIONS SECTION
5.1 Increased Bleeding Time
With some nonsteroidal anti-inflammatory drugs including ILEVRO™ (nepafenac ophthalmic suspension), 0.3%, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphema) in conjunction with ocular surgery.
It is recommended that ILEVRO™ (nepafenac ophthalmic suspension), 0.3% be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.
5.2 Delayed Healing
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) including ILEVRO™ (nepafenac ophthalmic suspension), 0.3%, 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.
5.3 Corneal Effects
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 topical NSAIDs including ILEVRO™ (nepafenac ophthalmic suspension), 0.3% 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 with topical NSAIDs also suggests that use more than 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk and severity of corneal adverse events.
5.4 Contact Lens Wear
ILEVRO™ (nepafenac ophthalmic suspension), 0.3% should not be administered while using contact lenses.
6 ADVERSE REACTIONS SECTION
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.
6.1 Serious and Otherwise Important Side Effects
The following adverse reactions are discussed in greater detail in other sections of labeling.
- Increased Bleeding Time (Warnings and Precautions 5.1)
- Delayed Healing (Warnings and Precautions 5.2)
- Corneal Effects (Warnings and Precautions 5.3)
6.2 Ocular Side Effects
The most frequently reported ocular adverse reactions following cataract surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. These reactions occurred in approximately 5 to 10% of patients.
Other ocular adverse reactions occurring at an incidence of approximately 1 to 5% included conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing and vitreous detachment.
Some of these reactions may be the consequence of the cataract surgical procedure.
6.3 Non-Ocular Side Effects
Non-ocular adverse reactions reported at an incidence of 1 to 4% included headache, hypertension, nausea/vomiting, and sinusitis.
8 USE IN SPECIFIC POPULATIONS SECTION
8.1 Pregnancy Section
Pregnancy Category C: 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 70 and 630 times human plasma exposure at the recommended human topical ophthalmic dose for rats and 20 and 180 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. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ILEVRO™ (nepafenac ophthalmic suspension), 0.3% 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 ILEVRO™ (nepafenac ophthalmic suspension), 0.3% during late pregnancy should be avoided.
8.3 Nursing Mothers Section
Nepafenac is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ILEVRO™ (nepafenac ophthalmic suspension), 0.3% is administered to a nursing woman.
8.4 Pediatric Use Section
The safety and effectiveness of ILEVRO™ (nepafenac ophthalmic suspension), 0.3% in pediatric patients below the age of 10 years have not been established.
8.5 Geriatric Use Section
No overall differences in safety and effectiveness have been observed between elderly and younger patients.
11 DESCRIPTION SECTION
ILEVRO™ (nepafenac ophthalmic suspension), 0.3% is a sterile, topical, nonsteroidal anti-inflammatory (NSAID) prodrug for ophthalmic use. Each mL of ILEVRO™ (nepafenac ophthalmic suspension), 0.3% contains 3 mg of nepafenac. Nepafenac is designated chemically as 2-amino-3-benzoylbenzeneacetamide with an empirical formula of C15H14N2O2. The structural formula of nepafenac is:
Nepafenac is a yellow crystalline powder. The molecular weight of nepafenac is 254.28. ILEVRO™ (nepafenac ophthalmic suspension), 0.3% is supplied as a sterile, aqueous suspension with a pH approximately of 6.8.
The osmolality of ILEVRO™ (nepafenac ophthalmic suspension), 0.3% is approximately 300 mOsm/kg.
Each mL of ILEVRO™ (nepafenac ophthalmic suspension), 0.3%, contains: Active:nepafenac 0.3% Inactives:boric acid, propylene glycol, carbomer 974P, sodium chloride, guar gum, carboxymethylcellulose sodium, edetate disodium, benzalkonium chloride 0.005% (preservative), sodium hydroxide and/or hydrochloric acid to adjust pH and purified water, USP.
12 CLINICAL PHARMACOLOGY SECTION
12.1 Mechanism of Action Section
After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a nonsteroidal anti-inflammatory drug. Nepafenac and amfenac are thought to inhibit the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.
12.3 Pharmacokinetics Section
Following bilateral topical ocular once-daily dosing of ILEVRO™ (nepafenac ophthalmic suspension), 0.3%, the concentrations of nepafenac and amfenac peaked at a median time of 0.5 hour and 0.75 hour, respectively on both Day 1 and Day 4. The mean steady-state Cmax for nepafenac and for amfenac were 0.847 ± 0.269 ng/mL and 1.13 ± 0.491 ng/mL, respectively.
Nepafenac at concentrations up to 3000 ng/mL and amfenac at concentrations up to 1000 ng/mL did not inhibit the in vitro metabolism of 6 specific marker substrates of cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Therefore, drug-drug interactions involving CYP mediated metabolism of concomitantly administered drugs are unlikely.
13 NONCLINICAL TOXICOLOGY SECTION
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Section
Nepafenac has not been evaluated in long-term carcinogenicity studies. Increased chromosomal aberrations were observed in Chinese hamster ovary cells exposed in vitro to nepafenac suspension. Nepafenac was not mutagenic in the Ames assay or in the mouse lymphoma forward mutation assay. Oral doses up to 5,000 mg/kg did not result in an increase in the formation of micronucleated polychromatic erythrocytes in vivo in the mouse micronucleus assay in the bone marrow of mice.
Nepafenac did not impair fertility when administered orally to male and female rats at 3 mg/kg.
14 CLINICAL STUDIES SECTION
In two double masked, randomized clinical trials in which patients were dosed daily beginning one day prior to cataract surgery, continued on the day of surgery and for the first two weeks of the postoperative period, ILEVRO™ (nepafenac ophthalmic suspension), 0.3% demonstrated superior clinical efficacy compared to its vehicle in treating postoperative pain and inflammation.
Treatment effect over vehicle for resolution of ocular pain occurred as early as day 1 post-surgery. Treatment effect over vehicle for resolution of inflammation was significantly better than vehicle in both studies at day 7 and day 14 post-surgery.
at Postop Day 14
|Ocular Pain Resolution
at Postop Day 14
|Study 1||Nepafenac ophthalmic suspension, 0.3% (n/N)(1)||552/851 (65%)||734/851 (86%)|
|NEVANAC (n/N)(1)||568/845 (67%)||737/845 (87%)|
|Vehicle (n/N)(1)||67/211 (32%)||98/211 (46%)|
|Difference (95% CI)(2)||33% (26%, 40%)||40% (32%, 47%)|
|Study 2||Nepafenac ophthalmic suspension, 0.3% (n/N)(1)||331/540 (61%)||456/540 (84%)|
|Vehicle (n/N)(1)||63/268 (24%)||101/268 (38%)|
|Difference (95% CI)(2)||38% (31%, 45%)||47% (40%, 54%)|
(1)n/N is the ratio of those with complete resolution of anterior chamber cell and flare by the postoperative day 14 visit over all randomized subjects.
(2)Difference is (Nepafenac ophthalmic suspension, 0.3% – vehicle). The 95% confidence interval is derived using asymptotic approximation.
16 HOW SUPPLIED/STORAGE AND HANDLING SECTION
ILEVRO™ (nepafenac ophthalmic suspension), 0.3% is supplied in a white, oval, low density polyethylene DROP-TAINER® dispenser with a natural low density polyethylene dispensing plug and gray polypropylene cap presented in an overwrap. Tamper evidence is provided with a shrink band around the closure and neck area of the package.
1.7 mL in 4 mL bottle NDC 0065-1750-07
Storage: Store at 2 - 25˚C (36 - 77˚F).
Protect from light.
17 PATIENT COUNSELING INFORMATION SECTION
17.1 Slow or Delayed Healing
Patients should be informed of the possibility that slow or delayed healing may occur while using nonsteroidal anti-inflammatory drugs (NSAIDs).
17.2 Avoiding Contamination of the Product
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
Use of the same bottle for both eyes is not recommended with topical eye drops that are used in association with surgery.
17.3 Contact Lens Wear
ILEVRO™ (nepafenac ophthalmic suspension), 0.3% should not be administered while wearing contact lens.
17.4 Intercurrent Ocular Conditions
Patients should be advised that if they develop an intercurrent ocular condition (e.g., trauma, or infection) or have ocular surgery, they should immediately seek their physician’s advice concerning the continued use of the multi-dose container.
17.5 Concomitant Topical Ocular Therapy
If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart.
17.6 Shake Well Before Use
Patients should be instructed to shake well before each use.
U.S. Patent Nos. 5,475,034; 6,403,609; and 7,169,767
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
© 2012 Novartis
PRINCIPAL DISPLAY PANEL
NDC 0065-1750-07 STERILE