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Ann Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 10.5144/0256-4947.2008.141asm-2-141LettersThe cardiovascular risks of etoricoxib (Arcoxia) Sasich Larry D. Barasain Mohammed A. Al Kudsi Mohammed A. From the Drug Information Pharmacists, Drug and Poison Information Center, Saudi Food and Drug Authority, Riyadh, Saudi ArabiaCorrespondence and reprints: Larry D. Sasich, Pharm.D., MPH, FASHP, Chair, Department of Pharmacy Practice, LECOM School of Pharmacy, 1858 West Grandview Blvd, Erie, PA 16509-1025 USA. Consultant, Saudi Food and Drug Authority, Riyadh, Saudi Arabia, T: 814-866-8467, F: 814-866-8450, lsasich@lecom.eduMar-Apr 2008 28 2 141 142 Copyright © 2008, Annals of Saudi Medicine2008This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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The selective COX-2 nonsteroidal anti-inflammatory drug etoricoxib (Arcoxia) was approved in Saudi Arabia in 2003 and re-registered in February 2007. The drug is now available in 63 countries worldwide. In April 2007, a U.S. Food and Drug Administration (FDA) advisory committee voted 20 to 1 not to recommend the approval of etoricoxib based on the drug’s cardiovascular (CV) risks and its association with an exacerbation of hypertension. 1 All information discussed by FDA advisory committees must be made available to the public before meetings. The advisory committee discussion documents, known as briefing documents, for the etoricoxib meeting can be found on the FDA’s Web site at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4290b1-01-FDA.pdf. Data presented at the committee meeting did not exclude the possibility of an over six-fold increase in CV risk with etoricoxib compared to naproxen.2 The original marketing application for etoricoxib was filed with the FDA in October 2001. In March 2002, the drug’s manufacturer withdrew the application to allow for the submission of additional data. The marketing application was again delayed in June 2002 when the FDA asked for additional acute pain efficacy and CV risk safety data. The FDA issued an approvable letter in October 2004 asking for additional safety and efficacy data before making a final decision on the drug’s marketing application.

In February 2005, two years prior to the approval of etoricoxib in Saudi Arabia, the FDA convened a meeting to review the safety of the COX-2 drugs, including etoricoxib. In the briefing documents for this meeting was an FDA safety review of etoricoxib and an analysis of the Etoricoxib vs. Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial.3 The EDGE results were originally presented at the American College of Rheumatology meeting in October 2004. The media reported that etoricoxib showed a significantly better gastrointestinal safety profile than diclofenac and no CV risk signal.4 The EDGE trial5 was not published until February 2007, at the same time the drug was re-registered in Saudi Arabia and over 28 months after public release of the results at the ACR meeting in October 2004.

The briefing documents for the February 2005 advisory committee meeting suggested that the drug does not offer a unique therapeutic advantage over existing drugs used for the treatment of osteoarthritis and may be associated with a significantly greater risk of CV adverse events compared to other agents.3 The question must be raised, if the February 2005 briefing documents were accessed by the Saudi Arabian drug regulatory authorities during the 2007 re-registration review of etoricoxib, would the drug have remained on the market in Saudi Arabia?

In summary, FDA briefing documents may contain rigorous analyses of unpublished data or data whose publication was delayed. These documents would appear to be important in the drug approval and re-registration processes in countries with evolving drug regulatory authorities or limited resources to commit to the drug approval process.
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REFERENCES
1 Harris GFDA   Rejects Merck’s New Pain Medication New York Times 2007 4 13 
2 Shibuya RB   Power Point Presentation - NDAs 21–389/772 Etoricoxib FDA Web site 2007 [cited 2007 Aug 12]; Available from: URL:http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4290s1-01-02-FDA-Shibuya.ppt  
3 Schiffenbauer J   Food and Drug Administration Briefing Package for NDA 21-389- Etoricoxib Food and Drug Administration report 2005 [cited 2007 Aug 16]; Available from: URL:http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_31_AA-FDA-Tab-T.pdf  
4 Medscape Medical News Discussion of rofecoxib data at ACR meeting, new data on etoricoxib Medscape 2004 [cited 2007 Aug 17]; Available from: URL:http://www.medscape.com/viewarticle/537974  
5 Baraf HS  Fuentealba C  Greenwald M  Brzezicki J  O’Brien K  Soffer B    Gastrointestinal side effects of etoricoxib in patients with osteoarthritis: results of the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial J Rheumatol 2007 34 408 20 17304660