Nepafenac

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Nepafenac
Nepafenac-2D-skeletal.svg
Clinical data
Trade namesAmnac, Ilevro
AHFS/Drugs.comMonograph
MedlinePlusa606007
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Ophthalmic
ATC code
Legal status
Legal status
Identifiers
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.207.414 Edit this at Wikidata
Chemical and physical data
FormulaC15H14N2O2
Molar mass254.28 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Nepafenac (brand name Nevanac or Ilevro) 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.[1] Nepafenac is a prodrug of amfenac, an inhibitor of COX-1 and COX-2 activity.[2][3]

Medical uses[edit]

Nepafenac is indicated for use in the treatment of pain and inflammation following cataract surgery.[1][4][5]The usual dose is one drop, thrice a day, in each affected eye beginning one day prior to cataract surgery, continued on the day of surgery and through the first two weeks of the postoperative period.[1]

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.[4] [5] Amfenac, like other NSAIDs, is thought to inhibit cyclooxygenase action. [4] [5]

Adverse events[edit]

Side effects include headache; runny nose; pain or pressure in the face; nausea; vomiting; and dry, itchy, sticky eyes.[6] 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.[6]

Regulatory[edit]

Nevanac[edit]

On February 25, 2005, Alcon filed an NDA with the FDA for Nevanac 0.1%.[7] 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.[8] Study C-02-53 consisted of 228 patients across 10 centers in the United States.[9] Study C-03-32 consisted of 522 patients across 22 centers in the United States. [9] The efficacy results presented were confirmed in a study published in 2007.[10]

Nevanac was approved by the FDA on August 19, 2005 with application number 021-862.[11]

Ilevro[edit]

An NDA for Ilevro was filed on December 15, 2011.[12] In a one-month study, no new toxicities arose in the new formulation of nepafenac.[13] Safety and efficacy information was derived from the previous Nevanac application.[13] In June 2010, a confirmatory study began (Study C09055) consisting of over 2000 patients from 49 US sites and 37 European sites.[14][15] 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.[14]

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

Commercialization[edit]

Both Nevanac and Ilevro are manufactured and sold by Alcon, Inc. [4][5]. Alcon is currently a division of Novartis International AG, which is primarily based out of Switzerland. [17] Alcon, Inc. also holds locations in both Switzerland and the United States.[18] The company has gone through several name changes, from Alcon Laboratories, Inc. to Alcon Universal, Ltd., to Alcon, Inc. [18]

Nevanac entered the market in 2005 as a product of Alcon, at the time a subsidiary of Nestlé.[19] On April 6, 2008, Novartis agreed to purchase approximately 74 million shares of Alcon from Nestlé at $143.18 per share.[19] 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.[19] At the time of the purchase, a proposal for a merger under Swiss merger law was given to the Alcon board of directors.[19] The merger was agreed upon on December 15, 2010, making Alcon "the second largest division within Novartis."[19] The merger was completed on April 8, 2011.[20]

Ilevro was launched by Alcon on January 21, 2013.[21] In 2014 and 2015, net sales by Alcon grew, contributed to in part by the increased volume in sales of Ilevro.[22][23][24] That financial year, Novartis reported $18 billion in total financial debt. [22] That figure has grown steadily since. In 2016, Novartis reported a total debt of $23.8 billion[25], up from the $21.9 billion reported in 2015 [24] and the $20.4 billion reported in 2014. [23] As of May 2017, Novartis is estimated to be worth $193.2 billion.[26]

On January 27, 2016, Alcon was moved to become a branch of the Innovative Medicines Division at Novartis.[25] Early in 2016, Alcon formed agreements with both TrueVision and PowerVision, and acquired Transcend Medical. [25] As of January 2017, Novartis is weighing options for Alcon in the business structure.[25]

Cost[edit]

As of 2015, roughly 266,751 Medicare Part D patients have been prescribed Ilevro as part of their therapeutic regimen for cataract surgery, earning Novartis approximately $95.2 million in 2015 from the 411,000 claims filed for the drug.[27] The average yearly cost for a Medicare Part D patient for Ilevro is $94.[27] The estimated per unit price in the United States for Nevanac is $88.93.[28] For Ilevro, the per unit price for the 1.7 mL bottle averages $156.89 and the per unit price for the 3 mL bottle averages $88.91.[29] Average price for both drugs is similar.[28][29]

Generic formulations are not yet available for either drug.[28][29]

Commercial risks[edit]

Alcon faced declining growth in 2016, having faced challenges in development and marketing of new products. [25]

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.[25] Novartis is also seeking to expand direct-to-consumer advertising and entrance into speciality product markets. [25] Novartis also notes the influence of position and preference on US Centers for Medicare & Medicaid formularies in expanding their market value. [25]

Nepafenac, Nevanac, and Ilevro are all absent from the 2016 Annual Report issued from Novartis.[25] Specific marketing aims for these drugs cannot be ascertained.

Intellectual property[edit]

There are currently 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 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 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]

Challenges[edit]

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.[41] The complaint was amended on June 14, 2017.[42]

References[edit]

  1. ^ a b c Nepafenac Monograph
  2. ^ Drugbank: Nepafenac
  3. ^ Lira, R. P.; Fulco, E. A.; Chaves, A.; Da Costa Pinto, F.; Arieta, F. R.; Lira, C. E. (2012). "Effect of preoperative use of topical prednisolone acetate, ketorolac tromethamine, nepafenac and placebo, on the maintenance of intraoperative mydriasis during cataract surgery: A randomized trial". Indian Journal of Ophthalmology. 60 (4): 277–281. doi:10.4103/0301-4738.98705. PMC 3442462. PMID 22824596.
  4. ^ a b c d "Nevanac (nepafenac) ophthalmic suspension label" (PDF). FDA. FDA. Retrieved 25 October 2017.
  5. ^ a b c d "Ilevro Full Prescribing Information" (PDF). Novartis. Novartis. Retrieved 25 October 2017.
  6. ^ a b "Nepafenac Ophthalmic". MedlinePlus. U.S. National Library of Medicine. Retrieved October 31, 2017.
  7. ^ "Nevanac Approval Package" (PDF). FDA. FDA. Retrieved October 31, 2017.
  8. ^ Gaynes, BI; Onyekwuluje, A (June 2008). "Topical ophthalmic NSAIDs: a discussion with focus on nepafenac ophthalmic suspension". Clinical ophthalmology (Auckland, N.Z.). 2 (2): 355–68. PMC 2693998. PMID 19668727.
  9. ^ a b "Nevanac Statistical Review" (PDF). FDA. FDA. Retrieved October 31, 2017.
  10. ^ 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.
  11. ^ "Drug Approval Package: Nevanac (Nepafenac) NDA #021862". FDA. FDA. Retrieved October 27, 2017.
  12. ^ "Ilevro Approval Package" (PDF). FDA. FDA. Retrieved October 31, 2017.
  13. ^ a b "203491 Pharmacology Review" (PDF). US FDA. FDA. Retrieved October 31, 2017.
  14. ^ a b "Ilevro Statistical Review" (PDF). FDA. FDA. Retrieved October 31, 2017.
  15. ^ "Confirmatory Study Nepafenac 0.3%". ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved October 31, 2017.
  16. ^ "Drug Approval Package: Nepafenac NDA #203491". FDA. FDA. Retrieved October 27, 2017.
  17. ^ "About Us". Novartis. Novartis. Retrieved October 27, 2017.
  18. ^ a b "Nevanac Administrative Documents and Correspondence" (PDF). FDA. FDA. Retrieved October 27, 2017.
  19. ^ a b c d e "Alcon Annual Report 2010" (PDF). SEC EDGAR. United States Securities and Exchange Commission. Retrieved October 30, 2017.
  20. ^ "Alcon Form 15". SEC EDGAR. United States Securities and Exchange Commission. Retrieved October 30, 2017.
  21. ^ "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. Alcon Global. Retrieved October 30, 2017.
  22. ^ a b "Form 20-F". SEC EDGAR. United States Securities and Exchange Commission. Retrieved October 30, 2017.
  23. ^ a b "Form 20-F". SEC EDGAR. United States Securities and Exchange Commission. Retrieved October 30, 2017.
  24. ^ a b "Form 20F". SEC EDGAR. United States Securities and Exchange Commission. Retrieved October 30, 2017.
  25. ^ a b c d e f g h i "Form 20-F". SEC EDGAR. United States Securities and Exchange Commission. Retrieved October 31, 2017.
  26. ^ "Novartis on the Forbes Top Multinational Performers List". Forbes.com. Forbes Media LLC. Retrieved October 31, 2017.
  27. ^ a b "Prescriber Checkup: Ilevro". Prescriber Checkup. ProPublica. Retrieved October 30, 2017.
  28. ^ a b c "Nevanac Prices, Coupons and Patient Assistance Programs". Drugs.com. Retrieved October 31, 2017.
  29. ^ a b c "Ilevro Prices, Coupons and Patient Assistance Programs". Drugs.com. Retrieved October 31, 2017.
  30. ^ "Nepafenac". U.S. Patents. PharmaCompass. Retrieved October 30, 2017.
  31. ^ "Generic Nevanac Availability". Drugs.com. Retrieved October 31, 2017.
  32. ^ a b "Generic Ilevro Availability". Drugs.com. Retrieved October 31, 2017.
  33. ^ "United States Patent Application: 6403609". United States Patent and Trademark Office. United States PTO. Retrieved October 31, 2017.
  34. ^ "United States Patent Application: 0060122277". United States Patent and Trademark Office. United States PTO. Retrieved October 30, 2017.
  35. ^ "United States Patent Application: 0060257487". United States Patent and Trademark Office. United States PTO. Retrieved October 27, 2017.
  36. ^ "United States Patent: 7947295". United States Patent and Trademark Office. United States PTO. Retrieved October 31, 2017.
  37. ^ "United States Patent: 8071648". United States Patent and Trademark Office. United States PTO. Retrieved October 31, 2017.
  38. ^ "United States Patent: 8921337". United States Patent and Trademark Office. United States PTO. Retrieved October 31, 2017.
  39. ^ "United States Patent: 9662398". United States Patent and Trademark Office. United States PTO. Retrieved October 31, 2017.
  40. ^ "Nepafenac - Generic Drug Details". DrugPatentWatch. thinkBiotech LLC. Retrieved October 31, 2017.
  41. ^ "Complaint". RPX Insight. RPX Corporation. Retrieved October 31, 2017.
  42. ^ "Amended Complaint". RPX Insight. RPX Corporation. Retrieved October 31, 2017.