Nepafenac

Nepafenac
Names
Trade namesNevanac, Ilevro, Amnac, others
IUPAC name
  • 2-amino-3-benzoylbenzeneacetamide
Clinical data
Drug classNSAID
Main usesPain and inflammation from cataract surgery[1]
Side effectsIrritation of the eye[1]
Pregnancy
category
  • AU: C[2]
  • US: C (Risk not ruled out)[2]
Routes of
use		Eye drops
External links
AHFS/Drugs.comMonograph
MedlinePlusa606007
Legal
License data
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Chemical and physical data
FormulaC15H14N2O2
Molar mass254.289 g·mol−1
3D model (JSmol)
SMILES
  • O=C(c1cccc(c1N)CC(=O)N)c2ccccc2
InChI
  • 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

Nepafenac, sold under the brand name Nevanac among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation associated with cataract surgery.[1] It is used as an eye drop.[1]

Common side effects include irritation of the eye.[1] Other side effects may include keratitis and hyphema.[3] It works by inhibiting COX-1 and COX-2 and therefore decreasing prostaglandins.[3][1]

Nepafenac was approved for medical use in the United States in 2005 and Europe in 2007.[3][1] In the United Kingdom a bottle costs the NHS about £15 as of 2021.[4] In the United States this amount costs about 290 USD.[5]

Medical uses

Nepafenac is indicated for use in the treatment of pain and inflammation following cataract surgery.[6][7][8][9]

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.[9]

Dosage

It is used once to three times per day depending on the strength of the formulation.[1] It is started once day before the surgery and continued for 2 to 9 weeks.[1]

Side effects

Eyelid redness after use of topical nepafenac in right eye (left eye normal)

Side effects include headache; runny nose; pain or pressure in the face; nausea; vomiting; and dry, itchy, sticky eyes.[10] 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.[10]

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.[7][8] Amfenac, like other NSAIDs, is thought to inhibit cyclooxygenase action.[7][8]

History

Nevanac

On February 25, 2005, Alcon filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for Nevanac 0.1%.[11] 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.[12] Study C-02-53 consisted of 228 patients across 10 centers in the United States.[13] Study C-03-32 consisted of 522 patients across 22 centers in the United States.[13] The efficacy results presented were confirmed in a study published in 2007.[14]

Nevanac was approved by the FDA on August 19, 2005, with application number 021–862.[15]

Ilevro

An NDA for Ilevro was filed on December 15, 2011.[16] In a one-month study, no new toxicities arose in the new formulation of nepafenac.[17] Safety and efficacy information was derived from the previous Nevanac application.[17] In June 2010, a confirmatory study began (Study C09055) consisting of over 2000 patients from 49 US sites and 37 European sites.[18][19] 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.[18]

Ilevro was approved by the FDA on October 16, 2012, with application number 203–491.[20]

Society and culture

Cost

This medication has a cost in Canada of $4.40 (per ml) for 10 ml ilevro oph 0.1 % [21]

  • Nepafenac costs (US)
    Nepafenac costs (US)
  • Nepafenac prescriptions (US)
    Nepafenac prescriptions (US)

Commercialization

Both Nevanac and Ilevro are manufactured and sold by Alcon, Inc.[7][8] Alcon is currently a division of Novartis International AG, which is primarily based out of Switzerland.[22] Alcon, Inc. also holds locations in both Switzerland and the United States.[23] The company has gone through several name changes, from Alcon Laboratories, Inc. to Alcon Universal, Ltd., to Alcon, Inc.[23]

Nevanac entered the market in 2005 as a product of Alcon, at the time a subsidiary of Nestlé.[24] On April 6, 2008, Novartis agreed to purchase approximately 74 million shares of Alcon from Nestlé at $143.18 per share.[24] 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.[24] At the time of the purchase, a proposal for a merger under Swiss merger law was given to the Alcon board of directors.[24] The merger was agreed upon on December 15, 2010, making Alcon "the second largest division within Novartis."[24] The merger was completed on April 8, 2011.[25]

Ilevro was launched by Alcon on January 21, 2013.[26] In 2014 and 2015, net sales by Alcon grew, contributed to in part by the increased volume in sales of Ilevro.[27][28][29] That financial year, Novartis reported $18 billion in total financial debt.[27] That figure has grown steadily since. In 2016, Novartis reported a total debt of $23.8 billion,[30] up from the $21.9 billion reported in 2015 [29] and the $20.4 billion reported in 2014.[28] As of May 2017, Novartis is estimated to be worth $193.2 billion.[31]

On January 27, 2016, Alcon was moved to become a branch of the Innovative Medicines Division at Novartis.[30] Early in 2016, Alcon formed agreements with both TrueVision and PowerVision, and acquired Transcend Medical.[30] As of January 2017, Novartis is weighing options for Alcon in the business structure.[30]

Alcon faced declining growth in 2016, having faced challenges in development and marketing of new products.[30]

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.[30] Novartis is also seeking to expand direct-to-consumer advertising and entrance into specialty product markets.[30] Novartis also notes the influence of position and preference on US Centers for Medicare & Medicaid formularies in expanding their market value.[30]

Nepafenac, Nevanac, and Ilevro are all absent from the 2016 Annual Report issued from Novartis.[30]

Intellectual property

There are currently seven U.S. patents filed that are directly associated with the modernized formulations of nepafenac, all stemming from Novartis.[32] There are three patents associated with Nevanac that are still active[33] and four associated with Ilevro.[34] The earliest patent related to the modern formulations of nepafenac was approved on June 11, 2002, after being filed in 1999, by Bahram Asgharian.[35] 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.[36] Another patent for a nepafenac-based drug was filed on May 8, 2006, by Geoffrey Owen, Amy Brooks, and Gustav Graff.[37] A patent was filed by Masood A. Chowhan and Huagang Chen on February 9, 2007, and approved on May 24, 2011,[38] followed closely by a patent filed by Warren Wong on September 23, 2010, and approved on December 6, 2011.[39] Masood A. Chowhan, Malay Ghosh, Bahram Asgharian, and Wesley Wehsin Han filed another patent on December 1, 2010, and approved on December 30, 2014.[40] 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.[41] These patents are in effect until dates ranging between July 17, 2018, and March 31, 2032.[34]

Novartis also maintains patents on nepafenac in 26 countries outside the United States.[42]

A lawsuit was filed by Alcon on March 4, 2016, against Watson Laboratories in Delaware for the manufacture of a generic version of the 0.3% nepafenac formulation, Ilevro.[43] The complaint was amended on June 14, 2017.[44]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Nevanac". Archived from the original on 7 July 2020. Retrieved 12 November 2021. Archived 7 July 2020 at the Wayback Machine
  2. ↑ 2.0 2.1 "Nepafenac ophthalmic Use During Pregnancy". Drugs.com. 6 June 2019. Archived from the original on 25 January 2021. Retrieved 13 September 2020. Archived 25 January 2021 at the Wayback Machine
  3. ↑ 3.0 3.1 3.2 "Nepafenac Monograph for Professionals". Drugs.com. Archived from the original on 22 April 2016. Retrieved 12 November 2021. Archived 22 April 2016 at the Wayback Machine
  4. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1206. ISBN 978-0857114105.
  5. ↑ "Nevanac Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 27 May 2020. Retrieved 12 November 2021. Archived 27 May 2020 at the Wayback Machine
  6. ↑ Nepafenac Monograph
  7. ↑ 7.0 7.1 7.2 7.3 "Nevanac- nepafenac suspension/ drops". DailyMed. 9 September 2019. Archived from the original on 6 July 2020. Retrieved 6 July 2020. Archived 6 July 2020 at the Wayback Machine
  8. ↑ 8.0 8.1 8.2 8.3 "Ilevro- nepafenac suspension". DailyMed. 9 September 2019. Archived from the original on 7 July 2020. Retrieved 6 July 2020. Archived 7 July 2020 at the Wayback Machine
  9. ↑ 9.0 9.1 "Nevanac EPAR". European Medicines Agency (EMA). Archived from the original on 7 July 2020. Retrieved 6 July 2020. Archived 7 July 2020 at the Wayback Machine
  10. ↑ 10.0 10.1 "Nepafenac Ophthalmic". MedlinePlus. U.S. National Library of Medicine. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  11. ↑ "Nevanac Approval Package" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on March 1, 2017. Retrieved October 31, 2017. Archived March 1, 2017, at the Wayback Machine
  12. ↑ Gaynes BI, Onyekwuluje A (June 2008). "Topical ophthalmic NSAIDs: a discussion with focus on nepafenac ophthalmic suspension". Clinical Ophthalmology. 2 (2): 355–68. doi:10.2147/opth.s1067. PMC 2693998. PMID 19668727.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ↑ 13.0 13.1 "Nevanac Statistical Review" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on February 18, 2017. Retrieved October 31, 2017. Archived February 18, 2017, at the Wayback Machine
  14. ↑ Lane SS, Modi SS, Lehmann RP, Holland EJ (January 2007). "Nepafenac ophthalmic suspension 0.1% for the prevention and treatment of ocular inflammation associated with cataract surgery". Journal of Cataract and Refractive Surgery. 33 (1): 53–8. doi:10.1016/j.jcrs.2006.08.043. PMID 17189793. S2CID 38881826.
  15. ↑ "Drug Approval Package: Nevanac (Nepafenac) Ophthalmic Suspension NDA #021862". U.S. Food and Drug Administration (FDA). January 6, 2005. Archived from the original on October 29, 2020. Retrieved October 27, 2017. Archived October 29, 2020, at the Wayback Machine
  16. ↑ "Ilevro Approval Package" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on March 1, 2017. Retrieved October 31, 2017. Archived March 1, 2017, at the Wayback Machine
  17. ↑ 17.0 17.1 "203491 Pharmacology Review" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on March 1, 2017. Retrieved October 31, 2017. Archived March 1, 2017, at the Wayback Machine
  18. ↑ 18.0 18.1 "Ilevro Statistical Review" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on February 28, 2017. Retrieved October 31, 2017. Archived February 28, 2017, at the Wayback Machine
  19. ↑ "Confirmatory Study Nepafenac 0.3%". ClinicalTrials.gov. U.S. National Library of Medicine. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  20. ↑ "Drug Approval Package: Nepafenac Ophthalmic Suspension, 0.3% NDA #203491". U.S. Food and Drug Administration (FDA). April 8, 2013. Archived from the original on April 3, 2021. Retrieved October 27, 2017. Archived April 3, 2021, at the Wayback Machine
  21. ↑ "Nepafenac (ilevro oph) Price Comparisons - Discounts, Cost & Coupons". PharmacyChecker.com. Archived from the original on 19 January 2021. Retrieved 5 April 2021. Archived 19 January 2021 at the Wayback Machine
  22. ↑ "About Us". Novartis. Archived from the original on September 1, 2017. Retrieved October 27, 2017. Archived September 1, 2017, at the Wayback Machine
  23. ↑ 23.0 23.1 "Nevanac Administrative Documents and Correspondence" (PDF). U.S. Food and Drug Administration (FDA). Archived (PDF) from the original on March 1, 2017. Retrieved October 27, 2017. Archived March 1, 2017, at the Wayback Machine
  24. ↑ 24.0 24.1 24.2 24.3 24.4 "Alcon Annual Report 2010" (PDF). SEC EDGAR. United States Securities and Exchange Commission. Archived (PDF) from the original on March 10, 2017. Retrieved October 30, 2017. Archived March 10, 2017, at the Wayback Machine
  25. ↑ "Alcon Form 15". SEC EDGAR. United States Securities and Exchange Commission. Archived from the original on November 7, 2017. Retrieved October 30, 2017. Archived November 7, 2017, at the Wayback Machine
  26. ↑ "Alcon Launches ILEVRO™ (nepafenac ophthalmic suspension) 0.3%, a New Non-Steroidal Anti-Inflammatory Drug, for the Treatment of Pain and Inflammation Associated with Cataract Surgery". Alcon. Archived from the original on December 15, 2018. Retrieved October 30, 2017. Archived December 15, 2018, at the Wayback Machine
  27. ↑ 27.0 27.1 "Form 20-F". SEC EDGAR. United States Securities and Exchange Commission. Archived from the original on December 15, 2018. Retrieved October 30, 2017. Archived December 15, 2018, at the Wayback Machine
  28. ↑ 28.0 28.1 "Form 20-F". SEC EDGAR. United States Securities and Exchange Commission. Archived from the original on October 18, 2017. Retrieved October 30, 2017. Archived October 18, 2017, at the Wayback Machine
  29. ↑ 29.0 29.1 "Form 20F". SEC EDGAR. United States Securities and Exchange Commission. Archived from the original on July 14, 2017. Retrieved October 30, 2017. Archived July 14, 2017, at the Wayback Machine
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 30.6 30.7 30.8 "Form 20-F". SEC EDGAR. United States Securities and Exchange Commission. Archived from the original on May 8, 2017. Retrieved October 31, 2017. Archived May 8, 2017, at the Wayback Machine
  31. ↑ "Novartis on the Forbes Top Multinational Performers List". Forbes. Archived from the original on November 14, 2017. Retrieved October 31, 2017. Archived November 14, 2017, at the Wayback Machine
  32. ↑ "Nepafenac". U.S. Patents. PharmaCompass. Archived from the original on November 7, 2017. Retrieved October 30, 2017. Archived November 7, 2017, at the Wayback Machine
  33. ↑ "Generic Nevanac Availability". Drugs.com. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  34. ↑ 34.0 34.1 "Generic Ilevro Availability". Drugs.com. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  35. ↑ "United States Patent Application: 6403609". United States Patent and Trademark Office. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  36. ↑ "United States Patent Application: 0060122277". United States Patent and Trademark Office. Archived from the original on August 29, 2021. Retrieved October 30, 2017. Archived August 29, 2021, at the Wayback Machine
  37. ↑ "United States Patent Application: 0060257487". United States Patent and Trademark Office. Archived from the original on August 29, 2021. Retrieved October 27, 2017. Archived August 29, 2021, at the Wayback Machine
  38. ↑ "United States Patent: 7947295". United States Patent and Trademark Office. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  39. ↑ "United States Patent: 8071648". United States Patent and Trademark Office. Archived from the original on August 29, 2021. Retrieved October 31, 2017. Archived August 29, 2021, at the Wayback Machine
  40. ↑ "United States Patent: 8921337". United States Patent and Trademark Office. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  41. ↑ "United States Patent: 9662398". United States Patent and Trademark Office. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  42. ↑ "Nepafenac - Generic Drug Details". DrugPatentWatch. thinkBiotech LLC. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  43. ↑ "Complaint". RPX Insight. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine
  44. ↑ "Amended Complaint". RPX Insight. Archived from the original on November 7, 2017. Retrieved October 31, 2017. Archived November 7, 2017, at the Wayback Machine

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