Nepafenac, sold under the brand name Nevanac among others, is a

nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents bl ...

(NSAID), usually sold as a prescription

eye drop Eye drops or eyedrops are liquid drops applied directly to the surface of the eye usually in small amounts such as a single drop or a few drops. Eye drops usually contain saline to match the salinity of the eye. Drops containing only saline ...

0.1% solution (Nevanac) or 0.3% solution (Ilevro). It is used to treat pain and inflammation associated with

cataract A cataract is a cloudy area in the lens (anatomy), lens of the eye that leads to a visual impairment, decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or ...

surgery.Nepafenac Nepafenac is a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

amfenac Amfenac, also known as 2-amino-3-benzoylbenzeneacetic acid, is a nonsteroidal anti-inflammatory drug (NSAID) with acetic acid moiety. See also * Bromfenac Bromfenac is a nonsteroidal anti-inflammatory drug (NSAID) marketed in the US as an o ...

, an inhibitor of

COX-1 Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 ( HUGO PTGS1), is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of three cyclooxygenases. History Cyclooxygenase (COX) is the centr ...

and

COX-2 Cyclooxygenase-2 (COX-2), also known as prostaglandin-endoperoxide synthase 2 ( HUGO PTGS2), is an enzyme that in humans is encoded by the ''PTGS2'' gene. In humans it is one of three cyclooxygenases. It is involved in the conversion of arachid ...

activity.

Medical uses

Nepafenac is indicated for use in the treatment of pain and inflammation following cataract surgery. In the European Union nepafenac is also indicated for the reduction in the risk of postoperative

macular edema Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye (a yellow central area of the retina) and causes it to thicken and swell ( edema). The swelling may distort a person's central vision, because the ma ...

associated with cataract surgery in people with diabetes.

Pharmacology

Mechanism of action

Nepafenac is an NSAID, thought to be a prodrug of amfenac after conversion by ocular tissue hydrolases after penetration via the

cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...

. Amfenac, like other NSAIDs, is thought to inhibit

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such a ...

action.

Adverse events

Side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

include headache; runny nose; pain or pressure in the face; nausea; vomiting; and dry, itchy, sticky eyes. Serious side effects include red or bloody eyes; foreign body sensation in the eye; sensitivity to light; decreased

visual acuity Visual acuity (VA) commonly refers to the clarity of visual perception, vision, but technically rates an animal's ability to recognize small details with precision. Visual acuity depends on optical and neural factors. Optical factors of the eye ...

; seeing specks or spots; teary eyes; or eye discharge or crusting.

Regulatory

Nevanac

On February 25, 2005, Alcon filed a

New Drug Application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

(NDA) with the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) for Nevanac 0.1%. 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. Study C-02-53 consisted of 228 patients across 10 centers in the United States. Study C-03-32 consisted of 522 patients across 22 centers in the United States. The efficacy results presented were confirmed in a study published in 2007. Nevanac was approved by the FDA on August 19, 2005, with application number 021–862.

Ilevro

An NDA for Ilevro was filed on December 15, 2011. In a one-month study, no new toxicities arose in the new formulation of nepafenac. Safety and efficacy information was derived from the previous Nevanac application. In June 2010, a confirmatory study began (Study C09055) consisting of over 2000 patients from 49 US sites and 37 European sites. 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. Ilevro was approved by the FDA on October 16, 2012, with application number 203–491.

Commercialization

Both Nevanac and Ilevro are manufactured and sold by

Alcon Alcon Inc. () is a Swiss-American pharmaceutical and medical device company specializing in eye care products. It has a paper headquarters in Geneva, Switzerland but its operational headquarters are in Fort Worth, Texas, United States, where it ...

, Inc. Alcon is currently a division of

Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...

International AG, which is primarily based out of Switzerland. Alcon, Inc. also holds locations in both Switzerland and the United States. The company has gone through several name changes, from Alcon Laboratories, Inc. to Alcon Universal, Ltd., to Alcon, Inc. Nevanac entered the market in 2005 as a product of Alcon, at the time a subsidiary of Nestlé. On April 6, 2008, Novartis agreed to purchase approximately 74 million shares of Alcon from Nestlé at $143.18 per share. 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. At the time of the purchase, a proposal for a merger under Swiss merger law was given to the Alcon board of directors. The merger was agreed upon on December 15, 2010, making Alcon "the second largest division within Novartis." The merger was completed on April 8, 2011. Ilevro was launched by Alcon on January 21, 2013. In 2014 and 2015, net sales by Alcon grew, contributed to in part by the increased volume in sales of Ilevro. That financial year, Novartis reported $18 billion in total financial debt. That figure has grown steadily since. In 2016, Novartis reported a total debt of $23.8 billion, up from the $21.9 billion reported in 2015 and the $20.4 billion reported in 2014. As of May 2017, Novartis is estimated to be worth $193.2 billion. On January 27, 2016, Alcon was moved to become a branch of the Innovative Medicines Division at Novartis. Early in 2016, Alcon formed agreements with both TrueVision and PowerVision, and acquired Transcend Medical. As of January 2017, Novartis is weighing options for Alcon in the business structure.

Commercial risks

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

Marketing

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. Novartis is also seeking to expand direct-to-consumer advertising and entrance into specialty product markets. Novartis also notes the influence of position and preference on US Centers for Medicare & Medicaid formularies in expanding their market value. Nepafenac, Nevanac, and Ilevro are all absent from the 2016 Annual Report issued from Novartis.

Intellectual property

There are currently seven U.S. patents filed that are directly associated with the modernized formulations of nepafenac, all stemming from Novartis. There are three patents associated with Nevanac that are still active and four associated with Ilevro. The earliest patent related to the modern formulations of nepafenac was approved on June 11, 2002, after being filed in 1999, by Bahram Asgharian. A patent was filed by Warren Wong, associated with Alcon, Inc. based out of

Fort Worth, Texas Fort Worth is a city in the U.S. state of Texas and the county seat of Tarrant County, Texas, Tarrant County, covering nearly into Denton County, Texas, Denton, Johnson County, Texas, Johnson, Parker County, Texas, Parker, and Wise County, Te ...

, on December 2, 2005, for aqueous suspensions of nepafenac. Another patent for a nepafenac-based drug was filed on May 8, 2006, by Geoffrey Owen, Amy Brooks, and Gustav Graff. A patent was filed by Masood A. Chowhan and Huagang Chen on February 9, 2007, and approved on May 24, 2011, followed closely by a patent filed by Warren Wong on September 23, 2010, and approved on December 6, 2011. Masood A. Chowhan, Malay Ghosh, Bahram Asgharian, and Wesley Wehsin Han filed another patent on December 1, 2010, and approved on December 30, 2014. The most recent 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. These patents are in effect until dates ranging between July 17, 2018, and March 31, 2032. Novartis also maintains patents on nepafenac in 26 countries outside the United States.

References

External links

* {{Portal bar , Medicine Acetamides 2-Aminobenzophenones Nonsteroidal anti-inflammatory drugs Drugs developed by Novartis Prodrugs Ophthalmology drugs