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Nepafenac
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Nepafenac
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Nepafenac
Clinical data
Trade namesNevanac, Ilevro, Amnac, others
AHFS/Drugs.comMonograph
MedlinePlusa606007
License data
Pregnancy
category
Routes of
administration		Topical eye drops
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)[2]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Identifiers
  • 2-amino-3-benzoylbenzeneacetamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.207.414 Edit this at Wikidata
Chemical and physical data
FormulaC15H14N2O2
Molar mass254.289 g·mol−1
3D model (JSmol)
  • O=C(c1cccc(c1N)CC(=O)N)c2ccccc2
  • InChI=1S/C15H14N2O2/c16-13(18)9-11-7-4-8-12(14(11)17)15(19)10-5-2-1-3-6-10/h1-8H,9,17H2,(H2,16,18) checkY
  • Key:QEFAQIPZVLVERP-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Nepafenac, sold under the brand name Nevanac among others, is a nonsteroidal anti-inflammatory drug (NSAID), usually sold as a prescription eye drop 0.1% solution (Nevanac) or 0.3% solution (Ilevro). It is used to treat pain and inflammation associated with cataract surgery.[3] Nepafenac is a prodrug of amfenac, an inhibitor of COX-1 and COX-2 activity.[4][5]

Medical uses

[edit]

Nepafenac is indicated for use in the treatment of pain and inflammation following cataract surgery.[3][6][7][8]

In the European Union nepafenac is also indicated for the reduction in the risk of postoperative macular edema associated with cataract surgery in people with diabetes.[8]

Pharmacology

[edit]

Mechanism of action

[edit]

Nepafenac is an NSAID, thought to be a prodrug of amfenac after conversion by ocular tissue hydrolases after penetration via the cornea.[6][7] Amfenac, like other NSAIDs, is thought to inhibit cyclooxygenase action.[6][7]

Adverse events

[edit]

Side effects include headache; runny nose; pain or pressure in the face; nausea; vomiting; and dry, itchy, sticky eyes.[9] Serious side effects include red or bloody eyes; foreign body sensation in the eye; sensitivity to light; decreased visual acuity; seeing specks or spots; teary eyes; or eye discharge or crusting.[9]

Regulatory

[edit]

Nevanac

[edit]

On February 25, 2005, Alcon filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for Nevanac 0.1%.[10] Results from the two trials referenced in the NDA (Phase 2/3 study C-02-53; Phase 3 study C-03-32) have not been published.[11] Study C-02-53 consisted of 228 patients across 10 centers in the United States.[12] Study C-03-32 consisted of 522 patients across 22 centers in the United States.[12] The efficacy results presented were confirmed in a study published in 2007.[13]

Nevanac was approved by the FDA on August 19, 2005, with application number 021–862.[14]

Ilevro

[edit]

An NDA for Ilevro was filed on December 15, 2011.[15] In a one-month study, no new toxicities arose in the new formulation of nepafenac.[16] Safety and efficacy information was derived from the previous Nevanac application.[16] In June 2010, a confirmatory study began (Study C09055) consisting of over 2000 patients from 49 US sites and 37 European sites.[17][18] A second phase 3 trial (Study C11003) was conducted in a population of 1,342 patients at 37 sites across the United States which failed to demonstrate superiority over Nevanac in an altered dosing regimen.[17]

Ilevro was approved by the FDA on October 16, 2012, with application number 203–491.[19]

Commercialization

[edit]

Both Nevanac and Ilevro are manufactured and sold by Alcon, Inc.[6][7] Alcon is currently a division of Novartis International AG, which is primarily based out of Switzerland.[20] Alcon, Inc. also holds locations in both Switzerland and the United States.[21] The company has gone through several name changes, from Alcon Laboratories, Inc. to Alcon Universal, Ltd., to Alcon, Inc.[21]

Nevanac entered the market in 2005 as a product of Alcon, at the time a subsidiary of Nestlé.[22] On April 6, 2008, Novartis agreed to purchase approximately 74 million shares of Alcon from Nestlé at $143.18 per share.[22] On January 4, 2010, Novartis agreed to purchase all remaining shares of Alcon from Nestlé, totalling 156 million shares or 77% of the shares in the company.[22] At the time of the purchase, a proposal for a merger under Swiss merger law was given to the Alcon board of directors.[22] The merger was agreed upon on December 15, 2010, making Alcon "the second largest division within Novartis."[22] The merger was completed on April 8, 2011.[23]

Ilevro was launched by Alcon on January 21, 2013.[24] In 2014 and 2015, net sales by Alcon grew, contributed to in part by the increased volume in sales of Ilevro.[25][26][27] That financial year, Novartis reported $18 billion in total financial debt.[25] That figure has grown steadily since. In 2016, Novartis reported a total debt of $23.8 billion,[28] up from the $21.9 billion reported in 2015 [27] and the $20.4 billion reported in 2014.[26] As of May 2017, Novartis is estimated to be worth $193.2 billion.[29]

On January 27, 2016, Alcon was moved to become a branch of the Innovative Medicines Division at Novartis.[28] Early in 2016, Alcon formed agreements with both TrueVision and PowerVision, and acquired Transcend Medical.[28] As of January 2017, Novartis is weighing options for Alcon in the business structure.[28]

Commercial risks

[edit]

Alcon faced declining growth in 2016, having faced challenges in development and marketing of new products.[28]

Marketing

[edit]

Novartis maintains a detailing unit geared toward health professionals consisting of over 3,000 employees within the United States and an additional 21,000 worldwide.[28] Novartis is also seeking to expand direct-to-consumer advertising and entrance into specialty product markets.[28] Novartis also notes the influence of position and preference on US Centers for Medicare & Medicaid formularies in expanding their market value.[28]

Nepafenac, Nevanac, and Ilevro are all absent from the 2016 Annual Report issued from Novartis.[28]

Intellectual property

[edit]

There are currently[when?] seven U.S. patents filed that are directly associated with the modernized formulations of nepafenac, all stemming from Novartis.[30] There are three patents associated with Nevanac that are still[when?] active[31] and four associated with Ilevro.[32] The earliest patent related to the modern formulations of nepafenac was approved on June 11, 2002, after being filed in 1999, by Bahram Asgharian.[33] A patent was filed by Warren Wong, associated with Alcon, Inc. based out of Fort Worth, Texas, on December 2, 2005, for aqueous suspensions of nepafenac.[34] Another patent for a nepafenac-based drug was filed on May 8, 2006, by Geoffrey Owen, Amy Brooks, and Gustav Graff.[35] A patent was filed by Masood A. Chowhan and Huagang Chen on February 9, 2007, and approved on May 24, 2011,[36] followed closely by a patent filed by Warren Wong on September 23, 2010, and approved on December 6, 2011.[37] Masood A. Chowhan, Malay Ghosh, Bahram Asgharian, and Wesley Wehsin Han filed another patent on December 1, 2010, and approved on December 30, 2014.[38] The most recent[when?] patent was filed by Masood A. Chowhan, Malay Ghosh, Bahram Asgharian, and Wesley Weshin Han on November 12, 2014, and approved on May 30, 2017.[39] These patents are in effect until dates ranging between July 17, 2018, and March 31, 2032.[32]

Novartis also maintains patents on nepafenac in 26 countries outside the United States.[40]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Nepafenac

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from Grokipedia
Nepafenac is a (NSAID) formulated as a sterile ophthalmic suspension for topical use in the eye, primarily indicated for the treatment and prevention of and following . It is marketed under brand names including Nevanac (0.1% concentration) and Ilevro (0.3% concentration), with the latter allowing for once-daily dosing to improve patient compliance, particularly beneficial for elderly patients who may experience forgetfulness or difficulty remembering multiple daily doses. As a , nepafenac is designed to enhance corneal penetration compared to other topical NSAIDs, enabling targeted delivery to ocular tissues. The involves rapid intraocular conversion of nepafenac to its , amfenac, by tissue hydrolases; amfenac then selectively inhibits both cyclooxygenase-1 (COX-1) and (COX-2) enzymes, thereby suppressing the production of prostaglandins that mediate , , and swelling in the anterior segment of the eye. Clinical studies have demonstrated its efficacy, with the 0.3% formulation resolving anterior chamber in approximately 68% of patients by day 14 post- compared to 34% with vehicle alone, and achieving -free status in over 90% of treated patients. Standard dosing regimens typically involve instilling one drop into the affected eye, starting one day before and continuing for two weeks afterward, with an optional additional drop 30 to 120 minutes prior to the procedure for the once-daily formulation. While generally well-tolerated, nepafenac carries risks associated with topical NSAIDs, including potential corneal adverse events such as superficial punctate or, rarely, more serious reactions like corneal thinning or perforation, particularly in patients with , , or those undergoing complicated ocular surgeries. Common side effects include , , and increased , and it is contraindicated in individuals with known to NSAIDs. Systemic absorption is minimal, resulting in low plasma concentrations that do not typically lead to significant drug interactions.

Medical Uses

Indications

Nepafenac is primarily indicated for the treatment of and associated with in adults. In the , it is also approved for reducing the risk of postoperative following in diabetic patients. of nepafenac has been reported for managing other ocular inflammatory conditions, such as cystoid , though evidence is limited and it lacks approval from regulatory bodies like the FDA for these purposes. The medication is intended for adult patients only, with safety and efficacy not established in children under 10 years of age. Caution is advised in patients with comorbidities such as bleeding tendencies, complicated ocular surgeries, corneal denervation, diabetes mellitus, ocular surface diseases, , or those undergoing repeat ocular surgeries, due to heightened risks of adverse corneal events.

Dosage and Administration

Nepafenac is available in two primary ophthalmic suspension formulations for the treatment of and inflammation associated with : Nevanac 0.1% and Ilevro 0.3%. For Nevanac 0.1%, the recommended dosage is one drop instilled into the affected eye three times daily, beginning one day prior to , continuing on the day of , and for the first two weeks postoperatively. For Ilevro 0.3%, the dosage is one drop once daily in the affected eye, starting one day before , on the day of , and for two weeks after; an additional drop should be administered 30 to 120 minutes prior to . The once-daily regimen of Ilevro is designed to improve patient compliance compared to three-times-daily alternatives such as Nevanac, which is particularly beneficial for elderly patients who may experience forgetfulness or difficulty remembering multiple daily doses. Manufacturer presentation slides often highlight this compliance advantage for elderly patients, while the official prescribing information does not specifically address forgetfulness but indicates no overall differences in safety or effectiveness in geriatric patients. Patients should shake the bottle well before each use to ensure proper suspension of the medication. To apply, tilt the head back slightly, pull down the lower to form a pocket, and instill the drop without allowing the dropper tip to touch the eye or any surface to prevent . Contact lenses should be removed before administration and may be reinserted 10 minutes after dosing, but nepafenac should not be used while wearing lenses during the treatment period. When used concomitantly with other topical ophthalmic medications, such as beta-blockers or cycloplegics, instill nepafenac at least five minutes apart to avoid dilution or washout effects. The typical duration of therapy is two weeks following , with no need for tapering unless directed by a healthcare provider.

Pharmacology

Chemical Properties

Nepafenac, with the systematic chemical name 2-amino-3-benzoylbenzeneacetamide, has the molecular formula C₁₅H₁₄N₂O₂ and a molecular weight of 254.28 g/mol. This compound is classified as a non-steroidal anti-inflammatory drug (NSAID) . Structurally, nepafenac is derived from amfenac, where the group is replaced by a carboxamide moiety, resulting in a yellow crystalline powder form. It does not exhibit polymorphism. Nepafenac demonstrates poor aqueous , with a reported value of approximately 0.014 mg/mL in at ambient conditions, necessitating its as a suspension for ophthalmic delivery. It is more soluble in organic solvents such as (≥5 mg/mL) and slightly soluble in and . Regarding stability, nepafenac remains stable under normal storage conditions at temperatures not exceeding 25°C, with protection from light recommended to maintain integrity over its .

Pharmacodynamics

Nepafenac is a that undergoes by ocular tissue hydrolases, primarily esterases, to form its , amfenac. This bioactivation occurs rapidly within the eye following topical administration, enabling targeted therapeutic effects. Amfenac exerts its primary mechanism of action by inhibiting both cyclooxygenase-1 (COX-1) and (COX-2) enzymes, thereby reducing the synthesis of prostaglandins from . This inhibition disrupts the pathway, leading to decreased ocular , pain, and the risk of conditions such as associated with elevated levels. Amfenac demonstrates greater potency against COX-2 compared to some other nonsteroidal drugs (NSAIDs), which contributes to its efficacy while the topical minimizes systemic exposure and associated gastrointestinal risks. The rapid corneal penetration of nepafenac facilitates quick intraocular accumulation of amfenac, achieving therapeutic concentrations within hours of application.

Pharmacokinetics

Nepafenac is administered topically to the eye as an ophthalmic suspension, allowing rapid penetration through the due to its lipophilic nature. Following bilateral topical ocular administration of 0.1% nepafenac three times daily, low but quantifiable plasma concentrations are observed, with mean steady-state maximum concentrations (Cmax) of approximately 0.31 ng/mL for nepafenac and 0.42 ng/mL for its amfenac. Systemic remains low, minimizing overall exposure beyond the ocular tissues. Distribution of nepafenac favors ocular compartments, achieving high intraocular concentrations of amfenac in the aqueous humor, with mean maximum concentrations of approximately 45 ng/mL reported after topical dosing in cataract surgery patients. Minimal accumulation occurs in plasma, and the drug exhibits moderate protein binding of 72-84% in human plasma. Ocular tissues such as the iris-ciliary body and retina-choroid serve as primary sites for prodrug activation and distribution. Nepafenac undergoes rapid conversion to the active metabolite amfenac via by intraocular tissue hydrolases, primarily in the iris-ciliary body and retina-choroid. Amfenac is further metabolized to inactive polar conjugates via and conjugation. This ensures targeted anti-inflammatory activity within the eye while limiting systemic effects. Elimination of nepafenac and its metabolites occurs primarily through renal excretion, with approximately 90% of an intravenous dose recovered in and within 24 hours in humans. The plasma half-life of amfenac is approximately 1-2 hours, and the plasma half-life of nepafenac is approximately 0.9 hours; steady-state concentrations are achieved by day 2 with multiple dosing regimens. No significant plasma accumulation is observed with repeated topical application. In special populations, pharmacokinetics show no clinically significant differences based on or race, as evidenced by comparable exposure profiles in toxicokinetic and clinical studies across Caucasian and Japanese subjects. Reduced clearance of amfenac may occur in patients with hepatic impairment due to involvement of hepatic enzymes in further , though the low systemic exposure generally mitigates clinical impact; specific dosing adjustments are not required.

Adverse Effects

Common Adverse Effects

The most common adverse effects of nepafenac, a topical ophthalmic , are primarily mild and ocular in nature, occurring due to its local application following . These effects typically affect 1% to 10% of patients and include foreign body sensation in the eye, sticky sensation, ocular hyperemia (redness), ocular discomfort (irritation), increased tearing (lacrimation), and decreased . Punctate has been reported in approximately 1% to 3% of patients, particularly in those with prolonged use or underlying conditions like . Less frequently, non-ocular systemic effects may occur at incidences of 1% to 4%, such as , or , and (which may manifest as nasopharyngitis-like symptoms including runny ). These effects are generally self-limiting and resolve spontaneously without intervention upon discontinuation of therapy. In post-surgical patients, nepafenac demonstrates a favorable overall safety profile, with most adverse effects being transient and related to the topical . Routine ocular examinations are recommended during therapy to monitor for any persistent symptoms.

Serious Adverse Effects

Serious adverse effects of nepafenac, though rare, primarily involve ocular complications that can lead to vision impairment, as well as potential systemic reactions in susceptible individuals. Ocular risks include corneal adverse events such as , which may progress to epithelial breakdown, corneal thinning, erosion, ulceration, or perforation, potentially resulting in sight-threatening outcomes. Punctate , a milder form, occurs at an incidence of approximately 1-3% in clinical trials, with higher rates (up to 3%) observed in diabetic patients during extended use; more severe complications such as thinning or perforation are rare and primarily identified through . has been reported rarely, at a frequency of 1 in 10,000 to 1 in 1,000 exposures. Vitreous floaters may occur in association with vitreous detachment, noted in 1-5% of patients in post-surgical settings, though not always directly attributable to the drug. Systemic risks encompass allergic reactions, including and, in patients sensitive to nonsteroidal anti-inflammatory drugs (NSAIDs), potential due to cross-sensitivity. Additionally, nepafenac may increase bleeding risk in surgical contexts by interfering with thrombocyte aggregation, leading to events such as . These serious reactions are rare. Prolonged use beyond 14 days post-surgery heightens the risk of delayed ocular healing, potentially exacerbating corneal complications. Incidences of serious events are derived from post-marketing surveillance, where frequencies are often not precisely quantifiable but indicate rare occurrences linked to extended or improper use. Suspected serious adverse events should be reported to the FDA via MedWatch at 1-800-FDA-1088 or www.fda.gov/medwatch.[](https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021862s017lbl.pdf)

Contraindications and Precautions

Contraindications

Nepafenac is contraindicated in patients with known to the active substance, any of the excipients in the formulation, or to other nonsteroidal anti-inflammatory drugs (NSAIDs). This includes individuals with a history of , urticaria, or acute exacerbated by acetylsalicylic acid (aspirin) or other NSAIDs, as may occur leading to severe allergic reactions.

Precautions

Use nepafenac with caution in patients with active epithelial herpetic keratitis or other viral infections affecting the or , as topical NSAIDs can impair corneal epithelial integrity, potentially exacerbating epithelial defects, delaying healing, ulceration, or . Close monitoring is advised, and discontinuation may be necessary if corneal issues arise. In surgical contexts, nepafenac should be used with caution in patients with bleeding disorders or those receiving anticoagulant therapy, with appropriate monitoring, as it may prolong by inhibiting platelet aggregation and increase the risk of intraoperative or postoperative hemorrhage. During , in the United States, nepafenac should be used only if the potential benefit justifies the potential risk to the (FDA narrative risk summary, as of 2020), as animal studies have shown adverse effects on fetal development with limited . It is contraindicated in the third trimester (after 30 weeks ) due to the potential for premature closure of the in the from inhibition. In the , use during is not recommended. For , in the , caution is advised due to limited on in milk despite minimal systemic exposure (FDA, 2020); in the , use is considered acceptable with no anticipated effects on the breastfed infant (EMA). Nepafenac is not approved for use in pediatric patients under 10 years of age , and and have not been established in children under 10 years; it is not recommended in the for those under 18 years due to insufficient data.

Drug Interactions

Nepafenac, a topical ophthalmic (NSAID), exhibits limited systemic drug interactions due to its low plasma concentrations following ocular administration. This low systemic exposure reduces the severity of potential interactions compared to oral NSAIDs. When used concomitantly with other topical ophthalmic medications, such as beta-blockers, inhibitors, alpha-agonists, cycloplegics, or mydriatics, nepafenac should be administered at least 5 minutes apart to minimize dilution or washout effects. Concomitant use with topical corticosteroids may increase the risk of delayed corneal healing. Similarly, concurrent administration with other topical NSAIDs can potentially exacerbate corneal adverse effects, such as epithelial breakdown or ulceration, due to additive inhibition of synthesis. Concomitant use with analogues is not recommended due to limited data and differing mechanisms that may affect . Systemically, nepafenac may enhance bleeding tendencies when co-administered with anticoagulants like or antiplatelet agents, due to its inhibitory effects on platelet aggregation. In such cases, monitoring of international normalized ratio (INR) is advised for patients on . Cross-sensitivity reactions may occur with other NSAIDs, including systemic formulations, potentially increasing the risk of gastrointestinal or renal adverse effects in susceptible individuals. Nepafenac and its amfenac do not significantly inhibit major (CYP) isozymes, including , , , , , and , at clinically relevant concentrations. Consequently, CYP-mediated drug interactions are unlikely. Protein binding interactions are also minimal. In patients on multiple medications (), management of potential interactions involves spacing ocular administrations, monitoring for bleeding or corneal issues, and considering dose adjustments or alternative therapies as clinically indicated.

Regulatory Status

Approvals in the United States

Nepafenac ophthalmic suspension was initially approved by the U.S. (FDA) on August 19, 2005, under the brand name Nevanac (0.1% concentration) for the treatment of and associated with . The approval was granted to , Inc., following a process, with the recommended dosing regimen of one drop three times daily, beginning one day prior to and continuing for 14 days postoperatively. A supplemental resulted in FDA approval of a higher-concentration , Ilevro (0.3% nepafenac ophthalmic suspension), on October 16, 2012, also by Research, Ltd. This approval supported once-daily dosing for the same indication, offering improved patient convenience based on demonstrating equivalent to the 0.1% at higher frequency. As a prescription-only ophthalmic nonsteroidal anti-inflammatory drug (NSAID), nepafenac is regulated by the FDA's Center for Drug Evaluation and Research, with ongoing required for post-marketing safety monitoring. The product labeling includes warnings under the "Warnings and Precautions" section regarding potential corneal adverse events, such as epithelial breakdown, , , ulceration, or , particularly with prolonged use beyond 14 days or in patients with complicating factors like or ; these risks have been emphasized in labeling since initial approval and updated in subsequent revisions to reflect post-marketing experience. The safety and effectiveness of nepafenac in pediatric patients below the age of 10 years have not been established, and pediatric exclusivity has not been granted by the FDA. As of November 2025, no generic versions of nepafenac ophthalmic suspension have been approved by the FDA .

Approvals in Europe

Nepafenac, marketed as Nevanac 0.1% suspension, received initial centralized marketing authorization from the (EMA) on 11 December 2007, valid throughout the for the prevention and treatment of postoperative pain and inflammation associated with in adults. In 2011, the EMA approved an expanded indication for Nevanac 0.1% to include the reduction in the risk of postoperative macular oedema associated with in adult patients with . The higher-strength formulation, Nevanac 0.3% (3 mg/ml) eye drops suspension, was approved via an extension of the marketing authorization in May 2013, supporting once-daily dosing for the prevention and treatment of postoperative pain and inflammation associated with in adults. In July 2016, the indication was further expanded to include the reduction in the risk of postoperative macular oedema associated with in adult patients with . As a centrally authorized , Nevanac is available and regulated uniformly across all member states under the EMA's oversight. Following the UK's exit from the on 31 December 2020, the EMA authorization for Nevanac was automatically converted to a separate Great Britain marketing by the Medicines and Healthcare products (MHRA), effective 1 January 2021, maintaining the existing indications without interruption.

Development and History

Research and Development

Nepafenac was developed by Laboratories during the mid-1990s as a derivative of amfenac, designed to overcome the limited corneal penetration of direct nonsteroidal drugs (NSAIDs) like amfenac itself. The compound, chemically known as 2-amino-3-benzoylbenzeneacetamide, features an linkage that enhances its , allowing better across the before enzymatic to the active amfenac within ocular tissues. This approach was specifically engineered to localize activation and thereby reduce systemic exposure compared to non- NSAIDs. Preclinical evaluations in animal models, including rabbits and rats, confirmed nepafenac's superior intraocular penetration and delivery of amfenac to anterior and posterior ocular segments relative to . assays demonstrated that amfenac exhibited greater potency in inhibiting (COX-2) than or , while maintaining activity against COX-1. These studies also established nepafenac's efficacy in reducing and in models of ocular trauma and inhibiting in oxygen-induced , supporting its potential for targeted effects without broad systemic absorption. Formulation efforts by centered on aqueous suspensions due to nepafenac's poor water solubility, with early work yielding a 0.1% suspension. Subsequent optimization led to a higher 0.3% suspension concentration, which extended the duration of therapeutic levels of amfenac in ocular tissues, enabling once-daily administration while preserving efficacy. Key development milestones included Alcon's filing of application IND #49,924 in February 1996, marking the transition from preclinical to planned human studies. The research was primarily conducted within Alcon's ophthalmic division, with limited involvement from external academic collaborators.

Clinical Trials

The pivotal clinical trials for nepafenac focused on its and in managing postoperative and following , as well as reducing the risk of in specific populations. For the 0.1% formulation (Nevanac), two double-masked, randomized, multicenter phase 3 trials involving a total of 837 patients demonstrated superior reduction compared to vehicle . In these studies, patients received one drop three times daily starting one day before , on the day of , and for 14 days postoperatively; approximately 80% of nepafenac-treated patients reported no ocular on postoperative day 1, compared to about 50% in the vehicle group, with sustained benefits through day 14. For the 0.3% formulation (Ilevro), phase 3 trials established non-inferiority to the 0.1% formulation while supporting once-daily dosing. In these studies, including C-09-055 (n=1907) and C-11-003 (n=808), once-daily nepafenac 0.3% was as effective as three-times-daily 0.1% in resolving (84-86% vs. 87% pain-free at day 14) and reducing anterior chamber , including cell and grades, with onset of as early as day 1 and control by day 7. Two larger double-masked, randomized trials (totaling over 2,400 patients across nepafenac 0.3%, 0.1%, and vehicle arms) confirmed these outcomes, showing 61-65% resolution of at day 14 versus 24-32% with vehicle. In diabetic patients at risk for postoperative , a European randomized, vehicle-controlled trial (n=252) supported nepafenac's approval for risk reduction. Patients received nepafenac 0.1% three times daily starting one day pre-surgery and continuing for up to 90 days postoperatively; the incidence of was 3.2% (4/125) in the nepafenac group versus 16.7% (21/125) in the vehicle group. Similar results were observed in integrated analyses of two phase 3 studies with the 0.3% formulation (n=594 diabetic patients), where occurred in 4.1% versus 15.9% with vehicle (p<0.001). Safety profiles across these trials were favorable, with low discontinuation rates of approximately 2% due to adverse events, primarily related to mild ocular irritation or hypersensitivity. Corneal adverse events, such as erosion or edema, occurred in less than 1% of patients overall. No phase 3 trials evaluated nepafenac beyond 14 days for standard indications or 90 days for macular edema prevention, though post-marketing surveillance studies continue to monitor long-term safety.

Commercialization

Brand Names and Formulations

Nepafenac is commercially available under the brand name Nevanac as a sterile, topical 0.1% ophthalmic suspension supplied in a 3 mL bottle. Ilevro is another branded formulation of nepafenac, provided as a 0.3% ophthalmic suspension in either 1.7 mL or 3 mL bottles; this higher concentration allows for reduced dosing frequency relative to the 0.1% suspension. In the , Nevanac is authorized as the 0.1% ophthalmic suspension, while in , both Nevanac (0.1%) and Ilevro (0.3%) are available. Nepafenac has no approved oral or injectable forms and is limited to ophthalmic suspension delivery. Commercial formulations of nepafenac are typically preserved with , and preservative-free options remain limited. Nevanac is formulated as an aqueous suspension with a pH of approximately 7.4, adjusted using and/or , along with excipients such as for and carbomer 974P as a . In contrast, Ilevro uses as a buffer in its aqueous suspension.

Manufacturers and Marketing

Alcon, Inc., serves as the primary manufacturer of nepafenac ophthalmic suspensions, including the branded products Nevanac and Ilevro, handling production for both the and global markets. Originally developed by , the company was acquired by Novartis International AG in 2011, becoming a until its spin-off as an independent entity in 2019, after which continued to oversee manufacturing and commercialization of nepafenac formulations. Distribution of nepafenac occurs exclusively through prescription channels, available via pharmacies, ophthalmic clinics, and specialized suppliers worldwide, ensuring controlled access for postoperative use. , Harrow Health, Inc., holds exclusive commercial rights to Nevanac and Ilevro following an agreement with in 2022 that closed in January 2023, facilitating targeted distribution to eye care providers. As of November 2025, no generic versions of nepafenac are approved or available in the US market. Alcon positioned nepafenac as a premium postoperative non-steroidal (NSAID) upon its launch, emphasizing its mechanism for enhanced penetration into ocular tissues and reduced inflammation following . Marketing efforts included direct-to-physician campaigns that highlighted these advantages over traditional NSAIDs, supported by educational initiatives for ophthalmologists to promote best practices in perioperative care. In the , Alcon's strategies extended to underscore nepafenac's approved indications for reducing the risk of associated with , through targeted promotions and as the marketing authorization holder. As of November 2025, branded nepafenac products remain the primary options in the and markets, with Alcon retaining market exclusivity for its branded products in the , supported by ongoing patent protections.

Intellectual Property

Alcon Research, Ltd., a of , Inc., holds several key patents covering nepafenac, including US Patent 5,475,034, which claims the prodrug composition for topical administration in treating inflammatory disorders. This patent, filed in 1993 and issued in 1995, expired on June 6, 2014, following patent term adjustments. Additional US patents protect specific formulations, such as US Patent 7,834,059 for topical ophthalmic suspension compositions, listed in the FDA Orange Book for Nevanac (NDA 021862). However, key patents for the 0.1% formulation, including US Patent 8,324,281, are set to expire on December 2, 2025. For the higher-concentration Ilevro formulation (NDA 203491), patents extend protection until March 31, 2032. Internationally, nepafenac is covered by a family spanning 23 countries, including the and , with 27 family members addressing composition, methods of use, and manufacturing processes. These protections vary by jurisdiction but generally align with expiration timelines for equivalent claims. Nepafenac received five-year exclusivity from the FDA upon approval of Nevanac in 2005, providing market protection until August 2010. Requests for pediatric exclusivity extensions were not granted, as no qualifying pediatric studies were submitted under FDA's Section 505A program. Patent challenges arose from generic manufacturers filing Abbreviated New Drug Applications (ANDAs), including Watson Laboratories' 2016 ANDA for a 0.3% nepafenac suspension, which certified Paragraph IV against Alcon's formulation and triggered infringement litigation in the District Court for the District of . Settlements in such cases have delayed generic entry, with no generics approved as of November 2025. As of November 2025, key formulation patents for the 0.1% suspension expire on December 2, 2025, and for the 0.3% version until 2032, supporting continued brand exclusivity without reported major ongoing disputes. These protections have postponed generic availability until at least late 2025.

References

  1. https://medlineplus.gov/druginfo/meds/a606007.html
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC5768593/
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021862s008lbl.pdf
  4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021862s017lbl.pdf
  5. https://www.ema.europa.eu/en/documents/product-information/nevanac-epar-product-information_en.pdf
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