RxFiles - Objective Comparisons for Optimal Drug Therapy

COXIB Links (related to media reports)

- Hepatic concerns: Prexige (lumiracoxib)

- lumiracoxib pulled from Canadian market following Health Canada review.  It was noted that there were 4 hepatic failure cases at the 100mg/day dose, 2 of which were in Canada.  (Oct 04, 2007)

- lumiracoxib pulled from Australian market due to liver deaths. (Aug 12, 2007): http://www.tga.gov.au/alerts/prexige.htmhttp://www.reuters.com/article/health-SP/idUSL1169646720070811;   http://abc.net.au/news/stories/2007/08/11/2002517.htm?section=justin 

- lumiracoxib - hepatic toxicity link to 200-400mg/day doses?? (Aug 2007) http://www.crikey.com.au/Politics/20070815-Prexige-and-liver-damage-were-Australian-patients-over-dosed.html; http://www.theaustralian.news.com.au/story/0,25197,22240814-23289,00.html 

-Initial Synopsis: Elevation of LFTs with lumiracoxib was seen in the TARGET trial, and was noted in the Health Canada  "Summary Basis of Decision" (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/phase1-decision/drug-med/sbd_smd_2007_prexige_102465_e.html).  Potential hepatic toxicity was dose related, seen especially at 200-400mg/day doses used.  Australia has now had some fatalities secondary to liver failure prompting the withdrawal of the drug from the Australian market.  It is important to note that strengths used in Australia appear to be 200mg or more.  In Canada, prescribing information and availability of the 100mg strength has likely resulted in lower strengths being used relative to Australia.  If using lumiracoxib, it would be prudent to avoid doses >100mg/day, and add liver function to list of cautions.  (RxFiles-Aug07)

- Summary from Rapid Rx & RxFiles (SHR) - Aug07: http://www.rxfiles.ca/acrobat/Lumiracoxib-Prexige-Hepatotoxicity-Aug2007.pdf 

- Summary (pdf) from SDIS (Saskatchewan Drug Information Service) - Aug07: http://www.rxfiles.ca/acrobat/Lumiracoxib-LFTs-SDIS-07.pdf 

- Cardiovascular concerns: Vioxx withdrawal etc.

Cardiovascular Risk of COX-2 Selective and Nonselective NSAIDs Oct. 2006: U. of S. College of Pharmacy - SDIS - Newsletter

Lessons of Vioxx June 23, 2005 NEJM  http://content.nejm.org/cgi/content/full/352/25/2576;  Insight on aggressive marketing of Vioxx after studies indicated risk (cardiovascular) including Merck documents.  http://www.democrats.reform.house.gov/story.asp?ID=848 

BEXTRA - Cardiovascular News Release Company Link (Oct 04)

"...In the letter to healthcare professionals, Pfizer also reviewed information about the cardiovascular profile of Bextra. The information is based on analyses of a comprehensive clinical trial database of nearly 8,000 patients treated with Bextra for durations ranging from six to 52 weeks. Available clinical information for Bextra suggests there is no increased risk of cardiovascular thromboembolic events in people treated for osteoarthritis (OA) and rheumatoid arthritis (RA).  In addition, Bextra has been studied in several surgical settings. In studies in general surgery, Bextra in combination with the investigational drug parecoxib (an IV formulation) showed no increased risk of cardiovascular thromboembolic events. However, in two trials in a high-risk surgery known as coronary artery bypass graft (CABG), an increase in cardiovascular events was observed in patients receiving Bextra alone or in combination with parecoxib..."  See link for complete article

Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med. 2005 May 9;165(9):978-84.

NEJM original articles & editorials from the 3 recent Cox-2 trials Feb 15, 2005  http://content.nejm.org/early_release/index.shtml#2-15 

FDA brief shows CV risk with etoricoxib and uncertainty over lumiracoxib (Food and Drug Administration Joint Meeting With the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee February 16-18, 2005 Briefing Information) 

David J Graham, David Campen, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study Lancet Published online January 25, 2005 http://www.thelancet.com/journal/vol365/iss9456/full/llan.365.9456.early_online_publication.32122.1 

More Evidence on Cardiovascular Risks of COX-2 Inhibitors (Four studies and an editorial in the Jan. 24,2005 issue of the Archives of Internal Medicine) http://www.medscape.com/viewarticle/498037    http://archinte.ama-assn.org/ 

"House of Coxibs" JAMA editorial, Dec 30 2004;  http://jama.ama-assn.org/cgi/content/full/293.3.366v1?etoc 

Health Canada Advisory - Bextra (valdecoxib), Celebrex (celecoxib), Mobicox (meloxicam); Dec 22, 2004: http://www.hc-sc.gc.ca/english/protection/warnings/2004/2004_69_e.html 

Naproxen warning of cardiac risks following an NIH sponsored Alzheimer's trial Dec20,2004.             http://www.fda.gov/bbs/topics/news/2004/NEW01148.html 

Celebrex (celecoxib) shown to have increase CV risk in one (APC trial) and not in the other (PreSAP trial) long term cancer trials on Dec 17,2004.             http://www.pfizer.com/are/investors_releases/2004pr/mn_2004_1217.cfm 

New FDA official Bextra (valdecoxib) contraindication in open heart surgery (CABG) patients on Dec 9,2004.     http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html

BMJ article criticizing Pfizer for delaying release of negative information about Bextra's heart adverse effects right away Oct 23, 2004.      http://bmj.bmjjournals.com/cgi/reprint/329/7472/935-a

Celebrex will conduct a 4000 patient over ~2yr trial to see if in fact the drug is safe in high cardiovascular risk osteoarthritis patients (since currently we do not have an answer for this question) on Oct 18,2004. 


Vioxx (rofecoxib) Withdrawal: Not a surprise to InfoPOEMs Nov 2001. 


Vioxx FDA submission which included MI data from the VIGOR trial on Feb ,8 2001.     http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_03_med.pdf


Interesting articles:

1:  Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. 
    Risk of cardiovascular events and rofecoxib: cumulative meta-analysis.

Lancet. 2004 Dec 4;364(9450):2021-9. PMID: 15582059 Conclusion: Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarize the accumulating evidence need to be clarified.

2:  Horton R.  Vioxx, the implosion of Merck, and aftershocks at the FDA. Lancet. 2004 
    Dec 4;364(9450):1995-6. PMID: 15582041]
3:  Oberholzer-Gee F, Inamdar SN.  Merck's recall of rofecoxib--a strategic 
    perspective.N Engl J Med. 2004 Nov 18;351(21):2147-9. PMID: 15548771]
4:  What about celebrex? Med Lett Drugs Ther. 2004 Oct 25;46(1194):87-8. PMID: 15520622 
5:  Topol EJ.  Failing the public health--rofecoxib, Merck, and the FDA.N Engl J Med. 
    2004 Oct 21;351(17):1707-9. Epub 2004 Oct 06. PMID: 15470193 
6:  Fitzgerald GA. Coxibs and cardiovascular disease.
    N Engl J Med. 2004 Oct 21;351(17):1709-11. Epub 2004 Oct 06. PMID: 15470192 
7:  Oberholzer-Gee F, Inamdar SN.  Merck's recall of rofecoxib--a strategic perspective. 
    N Engl J Med. 2004 Nov 18;351(21):2147-9. PMID: 15548771 
8:  Horton R.  Vioxx, the implosion of Merck, and aftershocks at the FDA. Lancet. 2004 
    Dec 4;364(9450):1995-6. PMID: 15582041 

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