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Etoricoxib

April 11, 2024

Etoricoxib, sold under the brand name Arcoxia, is a selective COX-2 inhibitor developed and commercialized by Merck. It is approved in 63 countries worldwide as of 2007, except the United States where the Food and Drug Administration sent a Non Approvable Letter to Merck and required them to provide additional data.[3]

Etoricoxib
Clinical data
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: C
  • Not recommended
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)[1]
  • BR: Class C1 (Other controlled substances)[2]
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability100%
Protein binding92%
MetabolismLiver, CYP extensively involved (mainly CYP3A4)
Elimination half-life22 hours
ExcretionKidney (70%) and fecal (20%)
Identifiers
  • 5-Chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine
CAS Number
  • 202409-33-4 Y
PubChem CID
  • 123619
IUPHAR/BPS
  • 2896
DrugBank
  • DB01628 Y
ChemSpider
  • 110209 Y
UNII
  • WRX4NFY03R
KEGG
  • D03710 Y
ChEBI
  • CHEBI:6339 Y
ChEMBL
  • ChEMBL416146 Y
CompTox Dashboard (EPA)
  • DTXSID3046457
ECHA InfoCard100.207.709
Chemical and physical data
FormulaC18H15ClN2O2S
Molar mass358.84 g·mol−1
3D model (JSmol)
  • Interactive image
  • O=S(=O)(c3ccc(c2cc(Cl)cnc2c1cnc(cc1)C)cc3)C
  • InChI=1S/C18H15ClN2O2S/c1-12-3-4-14(10-20-12)18-17(9-15(19)11-21-18)13-5-7-16(8-6-13)24(2,22)23/h3-11H,1-2H3 Y
  • Key:MNJVRJDLRVPLFE-UHFFFAOYSA-N Y
  (verify)

It was patented in 1996 and approved for medical use in 2002.[4]

Medical uses edit

Etoricoxib is indicated for "the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, and the pain and signs of inflammation associated with acute gouty arthritis."[5]

Efficacy edit

A Cochrane review assessed the benefits of single-dose etoricoxib in the reduction of acute post-operative pain in adults.[6] Single-dose oral etoricoxib provides four times more pain relief post-operatively than placebo, with equivalent levels of adverse events.[6] Etoricoxib given at a dose of 120 mg is as effective or even better than other analgesics that are commonly used.[6]

Adverse effects edit

Like all other NSAIDs, the COX-2 inhibitors too have their share of adverse effects. Fixed drug eruption and generalised erythema,[7] acute generalized exanthematous pustulosis (AGEP),[8] erythema multiforme like eruption[9] and drug induced pretibial erythema[10] are among the reported serious side effects.

Mechanism of action edit

Like any other selective COX-2 inhibitor ("coxib"), etoricoxib selectively inhibits isoform 2 of the enzyme cyclooxygenase (COX-2). It has approximately 106-fold selectivity for COX-2 inhibition over COX-1.[11] This reduces the generation of prostaglandins (PGs) from arachidonic acid. The clinical relevance of the drug stems from the role of PGs in the inflammation cascade.

Selective COX-2 inhibitors show less activity on COX-1 compared to traditional non-steroidal anti-inflammatory drugs (NSAID). This reduced activity is the cause of reduced gastrointestinal side effects, as demonstrated in several large clinical trials performed with different coxibs.[12][13]

Cardiovascular safety and concerns edit

Etoricoxib's safety on the gastrointestinal tract and cardiovascular was evaluated in the MEDAL Program consisting of three clinical trials: MEDAL (Multinational Etoricoxib Versus Diclofenac Arthritis Long-term Study), EDGE (Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness) and EDGE II.[14] Pooled analysis from these trials shows that etoricoxib has the same rates of thrombotic cardiovascular events as those of diclofenac, including thrombotic events (1.24 events per 100 patient-years with etoricoxib versus 1.3 events per 100 patient-years with diclofenac), arterial thrombotic events (1.05 events per 100 patient-years with etoricoxib versus 1.10 events per 100 patient-years with diclofenac) and risks of heart attack, stroke and death of vascular cause (0.84 per 100 patient-years with etoricoxib versus 0.87 events per 100 patient-years with diclofenac). Rates of upper gastrointestinal events (ulcer, bleeding, perforation, and obstruction) are in favor of the etoricoxib group (0.67 events per 100 patient-years with etoricoxib versus 0.97 events per 100 patient-years with diclofenac), but rates of complicated upper gastrointestinal events are similar between two groups.[15]

Like rofecoxib's VIGOR trial, the MEDAL Program was also criticized, this time due to Merck's choice of comparator group. In a testimony before the FDA Arthritis Advisory Committee, Sidney M. Wolfe pointed out that unlike the VIGOR trial, in which the active comparator was naproxen, three trials in the MEDAL Program used diclofenac as an active comparator. Wolfe showed that when compared etoricoxib to naproxen, which is a nonselective COX inhibitor, etoricoxib significantly increases the risks of cardiovascular events to such a degree that "are similar to rofecoxib/naproxen comparison", but when compared etoricoxib to diclofenac, which inhibits COX-2 more preferentially and has a worse CV safety profile than placebo, the difference was not statistically significant. He also noted the increase in other cardiac events, such as heart failure and high blood pressure.[16]

References edit

  1. ^ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  2. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). from the original on 3 August 2023. Retrieved 16 August 2023.
  3. ^ "Merck & Co., Inc. (Jobs) Receives Non Approvable Letter from FDA for Arcoxia (etoricoxib)". BioSpace. Retrieved 15 October 2023.
  4. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 522. ISBN 978-3-527-60749-5.
  5. ^ "Arcoxia - Article 6 (12) referral - Annex I, II, III, IV" (PDF). European Medicines Agency. 21 November 2008. Retrieved 15 October 2023.
  6. ^ a b c Clarke R, Derry S, Moore RA (May 2014). "Single dose oral etoricoxib for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews. 2019 (5): CD004309. doi:10.1002/14651858.CD004309.pub4. PMC 6485336. PMID 24809657.
  7. ^ Augustine M, Sharma P, Stephen J, Jayaseelan E (2006). "Fixed drug eruption and generalised erythema following etoricoxib". Indian Journal of Dermatology, Venereology and Leprology. 72 (4): 307–9. doi:10.4103/0378-6323.26732. PMID 16880582.
  8. ^ Mäkelä L, Lammintausta K (2008). "Etoricoxib-induced acute generalized exanthematous pustulosis". Acta Dermato-Venereologica. 88 (2): 200–1. doi:10.2340/00015555-0381. PMID 18311467.
  9. ^ Thirion L, Nikkels AF, Piérard GE (2008). "Etoricoxib-induced erythema-multiforme-like eruption". Dermatology. 216 (3): 227–8. doi:10.1159/000112930. PMID 18182814. S2CID 207645594.
  10. ^ Kumar P (December 2015). "Etoricoxib-induced pretibial erythema and edema". Indian Dermatology Online Journal. 6 (Suppl 1): S47-9. doi:10.4103/2229-5178.171046. PMC 4738517. PMID 26904451.
  11. ^ Riendeau D, Percival MD, Brideau C, Charleson S, Dubé D, Ethier D, et al. (February 2001). "Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2". The Journal of Pharmacology and Experimental Therapeutics. 296 (2): 558–566. PMID 11160644.
  12. ^ Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. (November 2000). "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group". The New England Journal of Medicine. 343 (21): 1520–8, 2 p following 1528. doi:10.1056/NEJM200011233432103. PMID 11087881.
  13. ^ Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, et al. (November 2006). "Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison". Lancet. 368 (9549): 1771–81. doi:10.1016/S0140-6736(06)69666-9. PMID 17113426. S2CID 18464206.
  14. ^ newera-admin (21 November 2011). "MEDAL Study (Multinational Etoricoxib Versus Diclofenac Arthritis Long-Term Study)". London Pain Clinic. Retrieved 15 October 2023.
  15. ^ Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, et al. (MEDAL Steering Committee) (November 2006). "Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison". Lancet. 368 (9549): 1771–1781. doi:10.1016/S0140-6736(06)69666-9. PMID 17113426. S2CID 18464206.
  16. ^ "Testimony Concerning Etoricoxib (Arcoxia)". Public Citizen. 12 April 2007. Retrieved 16 October 2023.

April 11, 2024
etoricoxib, sold, under, brand, name, arcoxia, selective, inhibitor, developed, commercialized, merck, approved, countries, worldwide, 2007, except, united, states, where, food, drug, administration, sent, approvable, letter, merck, required, them, provide, ad. Etoricoxib sold under the brand name Arcoxia is a selective COX 2 inhibitor developed and commercialized by Merck It is approved in 63 countries worldwide as of 2007 except the United States where the Food and Drug Administration sent a Non Approvable Letter to Merck and required them to provide additional data 3 EtoricoxibClinical dataAHFS Drugs comInternational Drug NamesPregnancycategoryAU C Not recommendedRoutes ofadministrationBy mouthATC codeM01AH05 WHO Legal statusLegal statusAU S4 Prescription only 1 BR Class C1 Other controlled substances 2 UK POM Prescription only Pharmacokinetic dataBioavailability100 Protein binding92 MetabolismLiver CYP extensively involved mainly CYP3A4 Elimination half life22 hoursExcretionKidney 70 and fecal 20 IdentifiersIUPAC name 5 Chloro 6 methyl 3 4 methylsulfonyl phenyl 2 3 bipyridineCAS Number202409 33 4 YPubChem CID123619IUPHAR BPS2896DrugBankDB01628 YChemSpider110209 YUNIIWRX4NFY03RKEGGD03710 YChEBICHEBI 6339 YChEMBLChEMBL416146 YCompTox Dashboard EPA DTXSID3046457ECHA InfoCard100 207 709Chemical and physical dataFormulaC 18H 15Cl N 2O 2SMolar mass358 84 g mol 13D model JSmol Interactive imageSMILES O S O c3ccc c2cc Cl cnc2c1cnc cc1 C cc3 CInChI InChI 1S C18H15ClN2O2S c1 12 3 4 14 10 20 12 18 17 9 15 19 11 21 18 13 5 7 16 8 6 13 24 2 22 23 h3 11H 1 2H3 YKey MNJVRJDLRVPLFE UHFFFAOYSA N Y verify It was patented in 1996 and approved for medical use in 2002 4 Contents 1 Medical uses 1 1 Efficacy 2 Adverse effects 3 Mechanism of action 4 Cardiovascular safety and concerns 5 ReferencesMedical uses editEtoricoxib is indicated for the symptomatic relief of osteoarthritis OA rheumatoid arthritis RA ankylosing spondylitis and the pain and signs of inflammation associated with acute gouty arthritis 5 Efficacy edit A Cochrane review assessed the benefits of single dose etoricoxib in the reduction of acute post operative pain in adults 6 Single dose oral etoricoxib provides four times more pain relief post operatively than placebo with equivalent levels of adverse events 6 Etoricoxib given at a dose of 120 mg is as effective or even better than other analgesics that are commonly used 6 Adverse effects editLike all other NSAIDs the COX 2 inhibitors too have their share of adverse effects Fixed drug eruption and generalised erythema 7 acute generalized exanthematous pustulosis AGEP 8 erythema multiforme like eruption 9 and drug induced pretibial erythema 10 are among the reported serious side effects Mechanism of action editLike any other selective COX 2 inhibitor coxib etoricoxib selectively inhibits isoform 2 of the enzyme cyclooxygenase COX 2 It has approximately 106 fold selectivity for COX 2 inhibition over COX 1 11 This reduces the generation of prostaglandins PGs from arachidonic acid The clinical relevance of the drug stems from the role of PGs in the inflammation cascade Selective COX 2 inhibitors show less activity on COX 1 compared to traditional non steroidal anti inflammatory drugs NSAID This reduced activity is the cause of reduced gastrointestinal side effects as demonstrated in several large clinical trials performed with different coxibs 12 13 Cardiovascular safety and concerns editEtoricoxib s safety on the gastrointestinal tract and cardiovascular was evaluated in the MEDAL Program consisting of three clinical trials MEDAL Multinational Etoricoxib Versus Diclofenac Arthritis Long term Study EDGE Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness and EDGE II 14 Pooled analysis from these trials shows that etoricoxib has the same rates of thrombotic cardiovascular events as those of diclofenac including thrombotic events 1 24 events per 100 patient years with etoricoxib versus 1 3 events per 100 patient years with diclofenac arterial thrombotic events 1 05 events per 100 patient years with etoricoxib versus 1 10 events per 100 patient years with diclofenac and risks of heart attack stroke and death of vascular cause 0 84 per 100 patient years with etoricoxib versus 0 87 events per 100 patient years with diclofenac Rates of upper gastrointestinal events ulcer bleeding perforation and obstruction are in favor of the etoricoxib group 0 67 events per 100 patient years with etoricoxib versus 0 97 events per 100 patient years with diclofenac but rates of complicated upper gastrointestinal events are similar between two groups 15 Like rofecoxib s VIGOR trial the MEDAL Program was also criticized this time due to Merck s choice of comparator group In a testimony before the FDA Arthritis Advisory Committee Sidney M Wolfe pointed out that unlike the VIGOR trial in which the active comparator was naproxen three trials in the MEDAL Program used diclofenac as an active comparator Wolfe showed that when compared etoricoxib to naproxen which is a nonselective COX inhibitor etoricoxib significantly increases the risks of cardiovascular events to such a degree that are similar to rofecoxib naproxen comparison but when compared etoricoxib to diclofenac which inhibits COX 2 more preferentially and has a worse CV safety profile than placebo the difference was not statistically significant He also noted the increase in other cardiac events such as heart failure and high blood pressure 16 References edit Prescription medicines registration of new generic medicines and biosimilar medicines 2017 Therapeutic Goods Administration TGA 21 June 2022 Retrieved 30 March 2024 Anvisa 31 March 2023 RDC Nº 784 Listas de Substancias Entorpecentes Psicotropicas Precursoras e Outras sob Controle Especial Collegiate Board Resolution No 784 Lists of Narcotic Psychotropic Precursor and Other Substances under Special Control in Brazilian Portuguese Diario Oficial da Uniao published 4 April 2023 Archived from the original on 3 August 2023 Retrieved 16 August 2023 Merck amp Co Inc Jobs Receives Non Approvable Letter from FDA for Arcoxia etoricoxib BioSpace Retrieved 15 October 2023 Fischer J Ganellin CR 2006 Analogue based Drug Discovery John Wiley amp Sons p 522 ISBN 978 3 527 60749 5 Arcoxia Article 6 12 referral Annex I II III IV PDF European Medicines Agency 21 November 2008 Retrieved 15 October 2023 a b c Clarke R Derry S Moore RA May 2014 Single dose oral etoricoxib for acute postoperative pain in adults The Cochrane Database of Systematic Reviews 2019 5 CD004309 doi 10 1002 14651858 CD004309 pub4 PMC 6485336 PMID 24809657 Augustine M Sharma P Stephen J Jayaseelan E 2006 Fixed drug eruption and generalised erythema following etoricoxib Indian Journal of Dermatology Venereology and Leprology 72 4 307 9 doi 10 4103 0378 6323 26732 PMID 16880582 Makela L Lammintausta K 2008 Etoricoxib induced acute generalized exanthematous pustulosis Acta Dermato Venereologica 88 2 200 1 doi 10 2340 00015555 0381 PMID 18311467 Thirion L Nikkels AF Pierard GE 2008 Etoricoxib induced erythema multiforme like eruption Dermatology 216 3 227 8 doi 10 1159 000112930 PMID 18182814 S2CID 207645594 Kumar P December 2015 Etoricoxib induced pretibial erythema and edema Indian Dermatology Online Journal 6 Suppl 1 S47 9 doi 10 4103 2229 5178 171046 PMC 4738517 PMID 26904451 Riendeau D Percival MD Brideau C Charleson S Dube D Ethier D et al February 2001 Etoricoxib MK 0663 preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase 2 The Journal of Pharmacology and Experimental Therapeutics 296 2 558 566 PMID 11160644 Bombardier C Laine L Reicin A Shapiro D Burgos Vargas R Davis B et al November 2000 Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis VIGOR Study Group The New England Journal of Medicine 343 21 1520 8 2 p following 1528 doi 10 1056 NEJM200011233432103 PMID 11087881 Cannon CP Curtis SP FitzGerald GA Krum H Kaur A Bolognese JA et al November 2006 Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long term MEDAL programme a randomised comparison Lancet 368 9549 1771 81 doi 10 1016 S0140 6736 06 69666 9 PMID 17113426 S2CID 18464206 newera admin 21 November 2011 MEDAL Study Multinational Etoricoxib Versus Diclofenac Arthritis Long Term Study London Pain Clinic Retrieved 15 October 2023 Cannon CP Curtis SP FitzGerald GA Krum H Kaur A Bolognese JA et al MEDAL Steering Committee November 2006 Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long term MEDAL programme a randomised comparison Lancet 368 9549 1771 1781 doi 10 1016 S0140 6736 06 69666 9 PMID 17113426 S2CID 18464206 Testimony Concerning Etoricoxib Arcoxia Public Citizen 12 April 2007 Retrieved 16 October 2023 Retrieved from https en wikipedia org w index php title Etoricoxib amp oldid 1216424456, wikipedia, wiki, book, books, library,

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