View source for Rofecoxib

{{Short description|Nonsteroidal anti-inflammatory drug}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| verifiedrevid = 470623576
| IUPAC_name = 4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one
| image = Rofecoxib.svg
| image_class = skin-invert-image
| width = 140
| image2 = Rofecoxib-3D.png
| image_class2 = bg-transparent <!-- unfortunately image has a white bg, it still can be fixed-->
<!--Clinical data-->
| pronounce = {{IPAc-en|ˌ|r|ɒ|f|ᵻ|ˈ|k|ɒ|k|s|ɪ|b}}
| tradename = Vioxx, Ceoxx, Ceeoxx, others
| pregnancy_AU = C
| legal_status = withdrawn  worldwide
| routes_of_administration = [[Oral administration|By mouth]] & i.m
<!--Pharmacokinetic data-->
| bioavailability = 93%
| protein_bound = 87%
| metabolism = liver
| elimination_half-life = 17 hours
| excretion = bile duct/kidney
<!--Identifiers-->
| IUPHAR_ligand = 2893
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 162011-90-7
| ATC_prefix = M01
| ATC_suffix = AH02
| ATC_supplemental =
| PubChem = 5090
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00533
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4911
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 0QTW8Z7MCR
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00568
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 8887
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 122
<!--Chemical data-->
| C=17 | H=14 | O=4 | S=1
| smiles = O=C2OCC(=C2\c1ccccc1)\c3ccc(cc3)S(=O)(=O)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H14O4S/c1-22(19,20)14-9-7-12(8-10-14)15-11-21-17(18)16(15)13-5-3-2-4-6-13/h2-10H,11H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RZJQGNCSTQAWON-UHFFFAOYSA-N
}}
'''Rofecoxib''' is a [[COX-2 inhibitor|COX-2-selective]] nonsteroidal anti-inflammatory drug ([[NSAID]]). It was marketed by [[Merck & Co.]] to treat [[osteoarthritis]], rheumatoid arthritis, juvenile rheumatoid arthritis, [[acute pain]] conditions, migraine, and [[dysmenorrhea]]. Rofecoxib was approved in the United States by the [[Food and Drug Administration]] (FDA) in May 1999, and was marketed under the brand names '''Vioxx''', '''Ceoxx''', and '''Ceeoxx'''. Rofecoxib was available by [[Medical prescription|prescription]] in both tablets and as an oral suspension.<ref name = "Vioxx PI">{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21647_vioxx_lbl.pdf|title=Vioxx PI|publisher=FDA|access-date=2019-03-27|archive-date=2013-08-22|archive-url=https://web.archive.org/web/20130822051659/https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21647_vioxx_lbl.pdf}}</ref>

Rofecoxib gained widespread use among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.<ref name="NPR_Merck_2004">{{citation |title=Merck Pulls Arthritis Drug Vioxx from Market |date=September 30, 2004 |url=https://www.npr.org/templates/story/story.php?storyId=4054991 | vauthors = Knox R |website=NPR.org | name-list-style = vanc |archive-url=https://web.archive.org/web/20101111103315/http://www.npr.org/templates/story/story.php?storyId=4054991 |archive-date=November 11, 2010 |access-date=December 24, 2016}}</ref>

In September 2004, Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of [[Myocardial infarction|heart attack]] and [[stroke]] associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, allegedly resulting in between 88,000 and 140,000 cases of serious heart disease in the US alone.<ref>{{cite news<!--double param: | work=Slate--> | url=https://www.newscientist.com/article/dn6918-up-to-140000-heart-attacks-linked-to-vioxx.html | title=Up to 140,000 heart attacks linked to Vioxx. | work=[[New Scientist]] | date=January 25, 2005 |page=1 }}</ref> Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.<ref>{{cite news | agency=Reuters | url=https://www.nytimes.com/2006/12/07/business/07drug.html?ex=1323147600&en=19d27b5814f1c1e8&ei=5088&partner=rssnyt&emc=rss | title=Merck Sees Slightly Higher 2007 Earnings | work=[[New York Times]] | date=December 7, 2006 | page=A1 | access-date=February 20, 2017 | archive-date=November 21, 2018 | archive-url=https://web.archive.org/web/20181121041016/https://www.nytimes.com/2006/12/07/business/07drug.html?ex=1323147600&en=19d27b5814f1c1e8&ei=5088&partner=rssnyt&emc=rss | url-status=live }}</ref>

In 2005, the FDA issued a memorandum concluding that risks for serious cardiovascular (CV) events seem to be as great for nonselective NSAIDs as for COX-2–selective agents such as rofecoxib, according to long-term, controlled clinical trials.<ref>{{Cite web|url=https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM106201.pdf|title=Analysis and recommendations for Agency action regarding nonsteroidal anti-inflammatory drugs and cardiovascular risk|website=FDA|access-date=2019-03-27|archive-date=2017-05-06|archive-url=https://web.archive.org/web/20170506134950/https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM106201.pdf}}</ref> Based on data up to 2015, the FDA reasserted the likelihood of an increased risk of serious adverse CV events from COX-2–selective and nonselective NSAIDs, dependent on dose and duration.<ref name="fda.gov">{{Cite web|url=https://www.fda.gov/Drugs/DrugSafety/ucm451800.htm|title=FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes|website=FDA|date=June 18, 2019|access-date=March 27, 2019|archive-date=March 27, 2019|archive-url=https://web.archive.org/web/20190327132023/https://www.fda.gov/Drugs/DrugSafety/ucm451800.htm}}</ref>

In November 2017, Massachusetts-based Tremeau Pharmaceuticals announced its plan to return rofecoxib (TRM-201) to market as a treatment for [[hemophilic arthropathy]] (HA). Tremeau announced that the FDA had granted an [[orphan drug|orphan]] designation for TRM-201 (rofecoxib) for the treatment of HA, and that they had received FDA feedback on their development plan.<ref name="Tremeau Pharmaceuticals News">{{Cite web|url=https://www.tremeaurx.com/news|title=Tremeau Pharmaceuticals News|website=Tremeau Pharmaceuticals|access-date=2019-03-27|archive-date=2019-03-27|archive-url=https://web.archive.org/web/20190327132024/https://www.tremeaurx.com/news|url-status=live}}</ref> HA is a degenerative joint disease caused by recurrent intra-articular bleeding. It is the largest cause of morbidity in patients with hemophilia and has no currently approved treatment options in the United States. Traditional NSAIDs are avoided in this population because of their effects on platelet aggregation and risk of gastrointestinal ulcers,<ref name="Srivastava e1–e47">{{cite journal | vauthors = Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A | title = Guidelines for the management of hemophilia | journal = Haemophilia | volume = 19 | issue = 1 | pages = e1-47 | date = January 2013 | pmid = 22776238 | doi = 10.1111/j.1365-2516.2012.02909.x | s2cid = 29659751 | doi-access = free }}</ref> and high potency opioids are the current standard of care in treating HA.<ref name="Forsyth 1549">{{cite journal | vauthors = Forsyth AL, Witkop M, Lambing A, Garrido C, Dunn S, Cooper DL, Nugent DJ | title = Associations of quality of life, pain, and self-reported arthritis with age, employment, bleed rate, and utilization of hemophilia treatment center and health care provider services: results in adults with hemophilia in the HERO study | journal = Patient Preference and Adherence | volume = 9 | pages = 1549–1560 | date = October 2015 | pmid = 26604708 | pmc = 4631419 | doi = 10.2147/PPA.S87659 | doi-access = free }}</ref>

{{TOC limit}}

==Mode of action==
{{See also|Cyclooxygenase}}
[[Cyclooxygenase]] (COX) has two well-studied isoforms, called COX-1 and COX-2. COX-1 mediates the synthesis of [[prostaglandins]] responsible for protection of the stomach lining, while COX-2 mediates the synthesis of prostaglandins responsible for pain and inflammation. By creating "selective" NSAIDs that inhibit COX-2, but not COX-1, the same pain relief as traditional NSAIDs is offered, but with greatly reduced risk of fatal or debilitating peptic ulcers. Rofecoxib is a selective [[COX-2 inhibitor]], or "coxib".

Though the class of coxibs includes several agents, degrees of COX-2 selectivity vary among them, with [[celecoxib]] (Celebrex) being the least COX-2 selective, and rofecoxib (Vioxx), [[valdecoxib]] (Bextra), and [[etoricoxib]] (Arcoxia), being highly COX-2 selective.<ref>{{cite journal | vauthors = Ushiyama S, Yamada T, Murakami Y, Kumakura S, Inoue S, Suzuki K, Nakao A, Kawara A, Kimura T | title = Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects | journal = European Journal of Pharmacology | volume = 578 | issue = 1 | pages = 76–86 | date = January 2008 | pmid = 17920584 | doi = 10.1016/j.ejphar.2007.08.034 }}</ref>

At the time of its withdrawal, rofecoxib was the only coxib approved in the United States with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and [[naproxen]].<ref name="Bombardier 2000">{{cite journal | vauthors = Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ | title = Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group | journal = The New England Journal of Medicine | volume = 343 | issue = 21 | pages = 1520–8, 2 p following 1528 | date = November 2000 | pmid = 11087881 | doi = 10.1056/NEJM200011233432103 | collaboration = VIGOR Study Group | doi-access = free }}</ref>

===Pharmacokinetics===
The therapeutic recommended dosages were 12.5, 25, and 50&nbsp;mg with an approximate bioavailability of 93%.<ref name = "Merck">{{cite web|url=http://www.merck.com/product/usa/pi_circulars/v/vioxx/vioxx_pi.pdf|title=VIOXX® (rofecoxib tablets and oral suspension): DESCRIPTION|publisher=Merck.com|access-date=4 January 2015|archive-date=21 October 2016|archive-url=https://web.archive.org/web/20161021203452/http://www.merck.com/product/usa/pi_circulars/v/vioxx/vioxx_pi.pdf}}</ref><ref name = "Gold">{{cite web|url=http://www.mdconsult.com/das/pharm/body/181267313-3/946823742/full/2399|title=MD Consult - Important Notice|publisher=Mdconsult.com|access-date=4 January 2015|archive-date=5 January 2015|archive-url=https://web.archive.org/web/20150105003909/http://www.mdconsult.com/das/pharm/body/181267313-3/946823742/full/2399|url-status=live}}</ref><ref name = "Davies">{{cite journal | vauthors = Davies NM, Teng XW, Skjodt NM | title = Pharmacokinetics of rofecoxib: a specific cyclo-oxygenase-2 inhibitor | journal = Clinical Pharmacokinetics | volume = 42 | issue = 6 | pages = 545–56 | year = 2003 | pmid = 12793839 | doi = 10.2165/00003088-200342060-00004 | s2cid = 23926296 }}</ref> Rofecoxib crossed the placenta and blood–brain barrier,<ref name = "Merck" /><ref name = "Gold" /><ref name = "Padi">{{cite journal | vauthors = Padi SS, Kulkarni SK | title = Differential effects of naproxen and rofecoxib on the development of hypersensitivity following nerve injury in rats | journal = Pharmacology Biochemistry and Behavior | volume = 79 | issue = 2 | pages = 349–58 | date = October 2004 | pmid = 15501312 | doi = 10.1016/j.pbb.2004.08.005 | s2cid = 22170590 }}</ref> and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) around 17 hours.<ref name = "Merck" /><ref name = "Davies" /><ref name = "Scott">{{cite journal | vauthors = Scott LJ, Lamb HM | title = Rofecoxib | journal = Drugs | volume = 58 | issue = 3 | pages = 499–505; discussion 506–7 | date = September 1999 | pmid = 10493277 | doi = 10.2165/00003495-199958030-00016 | s2cid = 219216087 }}</ref> The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib<ref name = "Merck" /><ref name = "Scott" /> which are primarily excreted through urine.

== Efficacy ==
Rofecoxib was approved by the FDA to treat [[osteoarthritis]], rheumatoid arthritis, juvenile rheumatoid arthritis, [[acute pain]] conditions, migraine, and [[dysmenorrhea]]. When it was marketed, it gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain.<ref name = "Vioxx PI" />

=== Premenstrual acne ===
A 2003 placebo-controlled, small, short-term study in India of 80 women with premenstrual [[acne vulgaris]], were given rofecoxib or placebo for two cycles of 10 days suggest that "rofecoxib is effective in the management of premenstrual acne.<ref>{{cite journal|vauthors=Tehrani R, Dharmalingam M|date=November 2004|title=Management of premenstrual acne with Cox-2 inhibitors: a placebo controlled study|url=http://www.ijdvl.com/article.asp?issn=0378-6323;year=2004;volume=70;issue=6;spage=345;epage=348;aulast=Tehrani|journal=Indian Journal of Dermatology, Venereology and Leprology|volume=70|issue=6|pages=345–8|pmid=17642660|access-date=2018-10-20|archive-date=2018-10-21|archive-url=https://web.archive.org/web/20181021111514/http://www.ijdvl.com/article.asp?issn=0378-6323;year=2004;volume=70;issue=6;spage=345;epage=348;aulast=Tehrani|url-status=live}}</ref>

===Fabricated efficacy studies===
On March 11, 2009, [[Scott Reuben|Scott S. Reuben]], former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as [[celecoxib]]) had been fabricated, overstating the analgesic effects of the drugs. No evidence has been found that Reuben colluded with Merck in falsifying his data. Reuben was also a former paid spokesperson for the drug company [[Pfizer]] (which owns the intellectual property rights for marketing celecoxib in the United States). The retracted studies were not submitted to either the FDA or the European Union's regulatory agencies prior to the drug's approval. Drug manufacturer [[Merck & Co.|Merck]] had no comment on the disclosure.<ref name="WSJ-3-2009">{{cite news | url=https://www.wsj.com/articles/SB123672510903888207?mod=loomia&loomia_si=t0:a16:g2:r1:c0.0270612:b22894832 | work=The Wall Street Journal | title=Top Pain Scientist Fabricated Data in Studies, Hospital Says | vauthors=Winstein KJ | date=March 11, 2009 | access-date=August 8, 2017 | archive-date=October 24, 2018 | archive-url=https://web.archive.org/web/20181024113201/https://www.wsj.com/articles/SB123672510903888207?mod=loomia&loomia_si=t0:a16:g2:r1:c0.0270612:b22894832 | url-status=live }}</ref><ref name="WSJ_Mathews_2004">{{citation |title=E-Mails Suggest Merck Knew Vioxx's Dangers at Early Stage As Heart-Risk Evidence Rose: Officials Played Hardball; Internal Message: 'Dodge!' |url=https://www.wsj.com/articles/SB109926864290160719 |vauthors=Mathews AW, Martinez B |publisher=Wall Street Journal |date=November 1, 2004 |access-date=March 11, 2017 |archive-date=October 24, 2018 |archive-url=https://web.archive.org/web/20181024152524/https://www.wsj.com/articles/SB109926864290160719 |url-status=live }}</ref>

==Side effects==
{{See also|Non-steroidal anti-inflammatory drug}}
[[Image:VIOXX sample blister pack.jpg|right|thumb|200px|A VIOXX (rofecoxib) sample blister pack]]

In addition to the reduced incidence of gastric ulceration, rofecoxib exhibits no effect on bleeding time or platelet aggregation, even at supratherapeutic doses.<ref>{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21647_vioxx_lbl.pdf|title=Vioxx PI|work=MERCK & CO., Inc.|publisher=U.S. Food and Drug Administration|access-date=2019-03-27|archive-date=2013-08-22|archive-url=https://web.archive.org/web/20130822051659/https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21647_vioxx_lbl.pdf|url-status=live}}</ref>  Aside from these features, rofecoxib exhibits a similar adverse-effect profile to other NSAIDs.

===Heart and blood vessels===

====VIGOR study and publishing controversy====
The Vioxx Gastrointestinal Outcomes Research (VIGOR) study led by Claire Bombardier compared the efficacy and adverse-effect profiles of a therapeutic dose of rofecoxib (50&nbsp;mg/day) vs. a common dose of naproxen (500&nbsp;mg/[[Bis in die|BID]]). The VIGOR study found that those on rofecoxib faced 4.25 times the relative risk of acute [[myocardial infarction]] as compared to those on naproxen over a mean duration of nine months. However, there was no significant difference in the mortality from cardiovascular events between the two groups. Furthermore, patients without high cardiovascular risk showed no significant difference in the rate of myocardial infarction between the treatment groups.<ref>{{Cite journal | vauthors = Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ | title = Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis | journal = New England Journal of Medicine | volume = 343 | issue = 21 | pages = 1520–1528 | date = 2000-11-23 | pmid = 11087881 | doi = 10.1056/NEJM200011233432103 | url = http://www.nejm.org/doi/abs/10.1056/NEJM200011233432103 | language = en | issn = 0028-4793 }}</ref>

Merck's scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks "is primarily due to" this protective effect.<ref name="Cardio">{{cite web|url=http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf|archive-url=https://web.archive.org/web/20150324043011/http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf|archive-date=24 March 2015|title=NAME OF DRUG: Rofecoxib (MK-0966): Memorandum|publisher=Fda.gov|access-date=4 January 2015}}</ref>{{citation needed|reason=primary resource only|date=March 2019}} The Martin Report excused senior management by stating they believed they were victims of Pfizer's alleged manipulation of test results to promote their product as a safer alternative.<ref>{{cite web|archive-url=https://web.archive.org/web/20101220235745/http://www.merck.com/newsroom/vioxx/pdf/020-appendix_h_criticism_of_vioxxs_renal_safety_profile.pdf|url=http://www.merck.com/newsroom/vioxx/pdf/020-appendix_h_criticism_of_vioxxs_renal_safety_profile.pdf| vauthors = Martin JS |publisher=Debevoise & Plimpton LLP|title=Report of John S. Martin, Jr. to the Special Committee of the Board of Directors of Merck & Co., Inc. Concerning the Conduct of Senior Management in the Development and Marketing of Vioxx: Appendix H|archive-date=December 20, 2010|date=September 5, 2006|page=2}}</ref> Some commentators have noted that naproxen would have to be three times as effective as [[aspirin]] to account for all of the difference,<ref>{{cite journal | title = DOUBT Is Their Product | vauthors = Michaels D | journal = Scientific American | volume = 292 | issue = 6 | date = June 2005 | pages = 96–101 | doi = 10.1038/scientificamerican0605-96 | pmid = 15934658 | bibcode = 2005SciAm.292f..96M | url = http://www.powerlinefacts.com/Sciam_article_on_lobbying.htm | archive-url = https://web.archive.org/web/20150104200843/http://www.powerlinefacts.com/Sciam_article_on_lobbying.htm| archive-date=January 4, 2015| url-access = subscription }}</ref> and some outside scientists warned Merck that this claim was implausible before VIGOR was published.<ref>{{cite web | title = Carlo Patrono on VIGOR | date = 2 March 2000 | work = Safe Drugs Now | url = http://www.saferdrugsnow.org/documents/vio/E-mailreCarloPatronoVIGOR.pdf | archive-url = https://web.archive.org/web/20060625011642/http://www.saferdrugsnow.org/documents/vio/E-mailreCarloPatronoVIGOR.pdf| archive-date=June 25, 2006}}</ref> No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin.<ref>{{cite journal | vauthors = Karha J, Topol EJ | title = The sad story of Vioxx, and what we should learn from it | journal = Cleveland Clinic Journal of Medicine | volume = 71 | issue = 12 | pages = 933–934 | date = December 2004 | pmid = 15641522 | doi = 10.3949/ccjm.71.12.933 | doi-broken-date = 31 July 2025 | s2cid = 19731479 }}</ref><ref>{{cite journal | vauthors = Solomon DH, Glynn RJ, Levin R, Avorn J | title = Nonsteroidal anti-inflammatory drug use and acute myocardial infarction | journal = Archives of Internal Medicine | volume = 162 | issue = 10 | pages = 1099–1104 | date = May 2002 | pmid = 12020178 | doi = 10.1001/archinte.162.10.1099 | doi-access = free }}</ref>

The results of the VIGOR study were submitted to the US FDA in February 2001. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, "Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four- to five-fold increase in myocardial infarctions (MIs) compared to patients on the comparator nonsteroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)."<ref>{{cite web|url=https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166383.pdf|title=Warning Letter|publisher=Fda.gov|access-date=4 January 2015|archive-date=10 March 2016|archive-url=https://web.archive.org/web/20160310191749/http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166383.pdf}}</ref> This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).

Months after the preliminary version of VIGOR was published in the ''[[New England Journal of Medicine]]'' in November 2000, the journal editors learned that certain data reported to the FDA were not included in the ''NEJM'' article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data.<ref name="Curfman 2006a">{{cite journal | vauthors = Curfman GD, Morrissey S, Drazen JM | title = Expression of concern: Bombardier et al., "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis," N Engl J Med 2000;343:1520-8 | journal = The New England Journal of Medicine | volume = 353 | issue = 26 | pages = 2813–4 | date = December 2005 | pmid = 16339408 | doi = 10.1056/NEJMe058314 | s2cid = 10745161 | doi-access = free }}</ref> They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. ''NEJM'' editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial.<ref>[https://www.forbes.com/work/feeds/ap/2006/02/13/ap2523250.html]{{dead link|date=January 2022|bot=medic}}{{cbignore|bot=medic}}</ref>

The editors charged that "more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article." These additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the "aspirin not indicated" group) and the editors noted that the omission "resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups." The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statistically insignificant). The editors also noted a statistically significant (two-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the ''NEJM'', though it had disclosed that information publicly in March 2000, eight months before publication.<ref name="Curfman 2006b">{{cite journal | vauthors = Curfman GD, Morrissey S, Drazen JM | title = Expression of concern reaffirmed | journal = The New England Journal of Medicine | volume = 354 | issue = 11 | page = 1193 | date = March 2006 | pmid = 16495386 | doi = 10.1056/NEJMe068054 | doi-access = free }}</ref>

The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection, thus were appropriately not included. (Using the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the "omitted" table were printed in the text of the article. The authors stood by the original article.<ref>{{cite journal | vauthors = Bombardier C, Laine L, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, Weaver A | title = Response to expression of concern regarding VIGOR study | journal = The New England Journal of Medicine | volume = 354 | issue = 11 | pages = 1196–9 | date = March 2006 | pmid = 16495387 | doi = 10.1056/NEJMc066096 }}</ref>

''NEJM'' stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks).<ref name="Curfman 2006b"/>

Some scientists have accused the ''NEJM'' editorial board of making unfounded accusations.<ref>{{cite web|vauthors=Lowe D|url=http://blogs.sciencemag.org/pipeline/archives/2006/02/22/nejm_vs_its_contributors_round_two/|title=NEJM vs. Its Contributors, Round Two|publisher=Science|access-date=20 November 2015|author-link=Derek Lowe (chemist)|date=2006-02-22|archive-date=2015-11-21|archive-url=https://web.archive.org/web/20151121234259/http://blogs.sciencemag.org/pipeline/archives/2006/02/22/nejm_vs_its_contributors_round_two|url-status=live}}</ref><ref>{{cite web | title = NEJM to Merck: we don't need no statistical significance | date = 24 February 2006 | vauthors = Hu J | work = Blogs for Industry | url = http://dimer.tamu.edu/simplog/archive.php?blogid=3&pid=3293 | archive-url = https://web.archive.org/web/20120610235819/http://dimer.tamu.edu/simplog/archive.php?blogid=3&pid=3293| archive-date=June 10, 2012}}</ref> Others have applauded the editorial. Renowned research cardiologist [[Eric Topol]],<ref>{{cite web | title = Eric Topol | url = http://genetics.case.edu/faculty2.php?fac=ejt9 | archive-url = https://web.archive.org/web/20060908042122/http://genetics.case.edu/faculty2.php?fac=ejt9| archive-date=September 8, 2006}}</ref> a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trial is really fully backed up".<ref>{{cite web | title = Cardiologist testifies Merck withheld data | url = http://archive.boston.com/business/healthcare/articles/2006/03/10/cardiologist_testifies_merck_withheld_data/ | work = Bloomberg News | via = Boston Globe | date = 10 March 2006 | access-date = 25 March 2023 | archive-date = 25 March 2023 | archive-url = https://web.archive.org/web/20230325105832/http://archive.boston.com/business/healthcare/articles/2006/03/10/cardiologist_testifies_merck_withheld_data/ | url-status = live }}</ref> Phil Fontanarosa, executive editor of the prestigious ''Journal of the American Medical Association'', welcomed the editorial, saying "this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies".<ref>{{cite web|url=http://www.beasleyallen.com/news/vioxx-plaintiffs-seek-mistrial-after-allegation-on-merck-study/|title=Vioxx Plaintiffs seek Mistrial after Allegation on Merck Study|work=Beasley Allen Law Firm |publisher=Beasleyallen.com|access-date=4 January 2015|date=2005-12-10|archive-date=2015-01-05|archive-url=https://web.archive.org/web/20150105004115/http://www.beasleyallen.com/news/vioxx-plaintiffs-seek-mistrial-after-allegation-on-merck-study/|url-status=live}}</ref>

On May 15, 2006, the ''[[Wall Street Journal]]'' reported that a late-night email, written by an outside public relations specialist and sent to ''Journal'' staffers hours before the Expression of Concern was released, predicted that "the rebuke would divert attention to Merck and induce the media to ignore the ''New England Journal of Medicine''{{'}}s own role in aiding Vioxx sales."<ref name="WSJ515">{{cite news | vauthors=Armstrong D | url=https://www.wsj.com/articles/SB114765430315252591 | title=How the New England Journal Missed Warning Signs on Vioxx | work=[[Wall Street Journal]] | date=2006-05-15 | page=A1 | access-date=2017-08-08 | archive-date=2018-11-20 | archive-url=https://web.archive.org/web/20181120074148/https://www.wsj.com/articles/SB114765430315252591 | url-status=live }}</ref>

"Internal emails show the ''New England Journal'''s expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal's handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article." The ''Journal'' stated that ''NEJM''{{'}}s "ambiguous" language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; "the ''New England Journal'' says it didn't attempt to have these mistakes corrected."<ref name="WSJ515"/> Investigations revealed that Merck had several years worth of information suggesting an elevated risk of cardiac events, and Vice President [[Edward Scolnick]] took much of the blame for the suppression of this information.<ref>{{Cite news|url=https://www.nytimes.com/2005/04/24/business/evidence-in-vioxx-suits-shows-intervention-by-merck-officials.html|title=Evidence in Vioxx Suits Shows Intervention by Merck Officials|vauthors=Berenson A|date=24 April 2005|via=NYTimes.com|newspaper=The New York Times|access-date=11 September 2017|archive-date=18 November 2018|archive-url=https://web.archive.org/web/20181118190317/https://www.nytimes.com/2005/04/24/business/evidence-in-vioxx-suits-shows-intervention-by-merck-officials.html|url-status=live}}</ref><ref>{{cite news|url=https://blogs.wsj.com/law/2006/02/08/the-merck-trial-edward-the-scalder-scolnick/|title=The Merck Vioxx Litigation: Edward "The Scalder" Scolnick|vauthors=Lattman P|newspaper=Wall Street Journa\|date=8 February 2006|access-date=24 April 2017|archive-date=24 October 2018|archive-url=https://web.archive.org/web/20181024112957/https://blogs.wsj.com/law/2006/02/08/the-merck-trial-edward-the-scalder-scolnick/}}</ref><ref>{{Cite web | vauthors = Presley H | title = Vioxx and the Merck team effort. | work = Kenan Center for Ethics at Duke University. 2009.|url=https://web.duke.edu/kenanethics/CaseStudies/Vioxx.pdf |access-date=2017-04-24 |archive-date=2017-04-25 |archive-url=https://web.archive.org/web/20170425120611/https://web.duke.edu/kenanethics/CaseStudies/Vioxx.pdf }}</ref>

The FDA reviewers were aware of the potential for cardiovascular risk in 1999<ref>{{cite web|url=https://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_06_G-FDA-Tab-D-2.pdf|archive-url=https://web.archive.org/web/20100310194639/https://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_06_G-FDA-Tab-D-2.pdf|date=April 30, 1999|archive-date=March 10, 2010|publisher=Food and Drug Administration: Centre for Drug Evaluation and Research:Division of Cardio-Renal Drug Products, HFD-110| vauthors = Pelayo JC |title=Consultation NDA 21-042. Cardiovascular and Renal Safety database.|page=4}}</ref><!--

"...cardiovascular and renal toxicities associated with MK-0966 when administered at a dosage ranging from 25 to 50 mg/daily, occur at a higher rate than with the other tested comparators, ie., ibuprofen; diclofenac; or nabumetone."

footnote 3:
"The assessment of the cardiovascular safety of MK-0966 was limited  to hyperintensive and edema related adverse events."

-->and it was argued that Merck had manipulated their EKG tests one week after the external review board provided their consultation to specifically exclude high risk factors from the trial subjects to avoid finding effect then predated the changes to their trials to almost three months earlier.<ref>{{cite journal|url=https://www.bmj.com/rapid-response/2011/11/01/re-selective-learning-0|date=November 1, 2011|journal=BMJ|title=What have we learnt from Vioxx? Re: On Selective Learning|vauthors=Egilman DS, Presler AH|volume=334|page=120|access-date=March 1, 2019|archive-date=March 1, 2019|archive-url=https://web.archive.org/web/20190301201513/https://www.bmj.com/rapid-response/2011/11/01/re-selective-learning-0|url-status=live}}</ref>

====Alzheimer's disease====
In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer's disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk from rofecoxib.<ref>{{cite journal | vauthors = Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, Gertz BJ | title = Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib | journal = Circulation | volume = 104 | issue = 19 | pages = 2280–2288 | date = November 2001 | pmid = 11696466 | doi = 10.1161/hc4401.100078 | doi-access = free }}</ref> Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib's safety.

====APPROVe study====
In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for the [[prophylaxis]] of [[polyp (medicine)|colorectal polyps]]. [[Celecoxib]] had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib, as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.{{citation needed|date=October 2018}}

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus [[placebo]], the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations.<ref name="Bresalier 2005">{{cite journal | vauthors = Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA | title = Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1092–102 | date = March 2005 | pmid = 15713943 | doi = 10.1056/NEJMoa050493 | collaboration = Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators | s2cid = 8161299 | doi-access = free }}</ref>

In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

====Other studies====
Preapproval phase III [[clinical trials]], like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first 18 months of rofecoxib usage (Merck, 2004). Others have pointed out that "study 090", a preapproval trial, showed a three-fold increase in cardiovascular events compared to placebo, a seven-fold increase compared to nabumetone (another NSAID), and an eight-fold increase in heart attacks and strokes combined compared to both control groups.<ref name="Cardio2">{{cite web|url=https://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf|archive-url=https://web.archive.org/web/20011218085732/https://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf|archive-date=18 December 2001|title=NAME OF DRUG: Rofecoxib (MK-0966): Memorandum|publisher=Fda.gov|access-date=4 January 2015}}</ref><ref>{{cite journal | vauthors = Kim PS, Reicin AS | title = Rofecoxib, Merck, and the FDA | journal = The New England Journal of Medicine | volume = 351 | issue = 27 | pages = 2875–8; author reply 2875–8 | date = December 2004 | pmid = 15625342 | doi = 10.1056/NEJM200412303512719 }}</ref> Although this was a relatively small study and only the last result was statistically significant, critics have charged that this early finding should have prompted Merck to quickly conduct larger studies of rofecoxib's cardiovascular safety. Merck notes that it had already begun VIGOR at the time Study 090 was completed. Although VIGOR was primarily designed to demonstrate new uses for rofecoxib, it also collected data on adverse cardiovascular outcomes.

Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using [[Kaiser Permanente]] data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005).

Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia.<ref name="cox2drugreview.org">{{cite journal | vauthors = Zhang J, Ding EL, Song Y | title = Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials | journal = JAMA | volume = 296 | issue = 13 | pages = 1619–32 | date = October 2006 | pmid = 16968832 | doi = 10.1001/jama.296.13.jrv60015 }}</ref>

====Other COX-2 inhibitors====
In 2005, the FDA issued a memo concluding that along with the other approved COX-2 selective NSAIDs available at the time (i.e., celecoxib, and valdecoxib), rofecoxib was associated with an increased risk of serious adverse cardiovascular events compared to placebo. They also noted that the available data did not permit a rank ordering of these drugs with regard to cardiovascular risk.<ref>{{Cite web|url=https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM106201.pdf|title=Analysis and recommendations for Agency action regarding nonsteroidal anti-inflammatory drugs and cardiovascular risk|website=FDA|access-date=2019-03-27|archive-date=2017-05-06|archive-url=https://web.archive.org/web/20170506134950/https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM106201.pdf}}</ref>

Only Celebrex (generic name is celecoxib) is still available for purchase in the United States.

Regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors:<ref name="EMEA2005">{{cite web |url=http://www.emea.europa.eu/pdfs/human/press/pr/20776605en.pdf |publisher=European Medicines Agency |title=European Medicines Agency concludes action on COX-2 inhibitors |access-date=2008-04-16 |archive-url=https://web.archive.org/web/20080406201636/http://www.emea.europa.eu/pdfs/human/press/pr/20776605en.pdf |archive-date=2008-04-06 }}</ref>

* Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease
* Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking
* Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment

====Other NSAIDs====
Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sorts of trials have never been carried out in older "trusted" NSAIDs such as [[ibuprofen]], [[diclofenac]] and others. The possible exceptions may be [[aspirin]] and [[naproxen]] because of their anti-platelet aggregation properties.

Analyses in 2011 and 2013 by McGettigan and the Coxib and traditional NSAID Trialists (CNT) Collaborators, respectively, demonstrated that the risk of serious CV events was a dose dependent effect of COX-2 selective and nonselective NSAIDs, with the possible exception of naproxen, and high therapeutic doses of nonselective NSAIDs (e.g. ibuprofen 2400&nbsp;mg/day, diclofenac 150&nbsp;mg/day) carried similar CV risk when compared to a combined group of therapeutic and supra-therapeutic doses of COX-2 selective  NSAIDs (such as rofecoxib).<ref>{{cite journal | vauthors = McGettigan P, Henry D | title = Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies | journal = PLOS Medicine | volume = 8 | issue = 9 | article-number = e1001098 | date = September 2011 | pmid = 21980265 | pmc = 3181230 | doi = 10.1371/journal.pmed.1001098 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C | title = Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials | journal = Lancet | volume = 382 | issue = 9894 | pages = 769–779 | date = August 2013 | pmid = 23726390 | pmc = 3778977 | doi = 10.1016/s0140-6736(13)60900-9 | collaboration = Coxib traditional NSAID Trialists' (CNT) Collaboration }}</ref>

In 2014, Patrono and Baigent, summarizing all of the currently available data in a review article in Circulation, concluded that with the exception of GI toxicity, neither the efficacy nor the major cardiorenal complications of COX-2 selective NSAIDs appear to be influenced by their level of COX-2 selectivity. They concluded that the CV risk associated with NSAIDs was dependent on dose and duration.<ref>{{cite journal | vauthors = Patrono C, Baigent C | title = Nonsteroidal anti-inflammatory drugs and the heart | journal = Circulation | volume = 129 | issue = 8 | pages = 907–916 | date = February 2014 | pmid = 24566065 | doi = 10.1161/circulationaha.113.004480 | doi-access = free }}</ref>

This conclusion was further reinforced by the 2016 results of the celecoxib PRECISION trial, which showed no difference in CV event rates between the COX-2 selective NSAID celecoxib and the non-selective NSAIDs ibuprofen and naproxen.<ref>{{cite journal | vauthors = Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME, Graham DY, Borer JS, Wisniewski LM, Wolski KE, Wang Q, Menon V, Ruschitzka F, Gaffney M, Beckerman B, Berger MF, Bao W, Lincoff AM | title = Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis | journal = The New England Journal of Medicine | volume = 375 | issue = 26 | pages = 2519–2529 | date = December 2016 | pmid = 27959716 | doi = 10.1056/nejmoa1611593 | doi-access = free }}</ref>

==Withdrawal==
As a result of the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.<ref>{{cite web |url=http://www.merck.com/newsroom/vioxx/pdf/vioxx_press_release_final.pdf |title=Merck Announces Voluntary Worldwide Withdrawal of VIOXX |publisher=Merck.com |access-date=4 January 2015 |archive-url=https://web.archive.org/web/20120417053059/http://www.merck.com/newsroom/vioxx/pdf/vioxx_press_release_final.pdf |archive-date=17 April 2012 }}</ref><ref name="NPR_2004">{{citation |url=https://www.npr.org/templates/story/story.php?storyId=4054991 |work=National Public Radio (NPR) |date=2004 |title=Q&A on the case, following withdrawal announcement |access-date=December 24, 2016 |archive-date=November 11, 2010 |archive-url=https://web.archive.org/web/20101111103315/http://www.npr.org/templates/story/story.php?storyId=4054991 |url-status=live }}</ref>

In addition to its own studies, on September 23, 2004, Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). One FDA analyst estimated that, based upon his mathematical model, Vioxx may have caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market. Senior FDA officials were quick to note, however, that this estimate was based solely on a mathematical model, and must be interpreted with caution. His analysis only concerned Americans.<ref>{{cite web|url=https://www.pbs.org/newshour/show/congress-questions-vioxx-fda|title=Congress Questions Vioxx, FDA|date=2004-11-18|work=[[PBS NewsHour]]|access-date=2013-06-03|archive-date=2019-04-23|archive-url=https://web.archive.org/web/20190423170157/https://www.pbs.org/newshour/show/congress-questions-vioxx-fda|url-status=live}}</ref>

On November 5, 2004, the medical journal ''[[The Lancet]]'' published a [[meta-analysis]] of the available studies on the safety of rofecoxib<ref name="Jüni_2004_Lancet">{{cite journal | vauthors = Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M | title = Risk of cardiovascular events and rofecoxib: cumulative meta-analysis | journal = Lancet | volume = 364 | issue = 9450 | pages = 2021–9 | year = 2004 | pmid = 15582059 | doi = 10.1016/S0140-6736(04)17514-4 | s2cid = 9780851 }}</ref> (Jüni ''et al.'', 2004). The authors concluded that, owing to the known [[cardiovascular]] risk, rofecoxib should have been withdrawn several years earlier. ''The Lancet'' published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall.<ref>{{cite web |url=http://www.thelancet.com/journal/vol364/iss9446/full/llan.364.9446.early_online_publication.31178.1 |title=The Journal: Current Issue |website=www.thelancet.com |access-date=17 January 2022 |archive-url=https://web.archive.org/web/20041107035721/http://www.thelancet.com/journal/vol364/iss9446/full/llan.364.9446.early_online_publication.31178.1 |archive-date=7 November 2004 }}</ref><ref name="Lancet_Implosion_Merck_2004">{{cite journal | vauthors = Horton R | title = Vioxx, the implosion of Merck, and aftershocks at the FDA | journal = Lancet | volume = 364 | issue = 9450 | pages = 1995–6 | year = 2004 | pmid = 15582041 | doi = 10.1016/S0140-6736(04)17523-5 | s2cid = 45771 }}</ref> Merck responded by issuing a rebuttal of the Jüni ''et al.'' meta-analysis that noted that Jüni omitted several studies that showed no increased cardiovascular risk.<ref>Merck & Co., 2004{{full citation needed|date=October 2018}}</ref>

===Martin Report===
In 2005, Merck spent $21 million to retain [[John S. Martin Jr.]], a former District Judge for the [[United States District Court for the Southern District of New York|Southern District of New York]], and his firm, [[Debevoise & Plimpton]], to investigate the Vioxx study results and Merck communications.<ref name=nothing_wrong>{{cite news |title='Merck Did Nothing Wrong,' Martin Report says |url=http://www.pharmexec.com/merck-did-nothing-wrong-martin-report-says |access-date=27 January 2019 |publisher=Pharmaceutical Executive |date=Sep 13, 2006 |archive-date=27 January 2019 |archive-url=https://web.archive.org/web/20190127094458/http://www.pharmexec.com/merck-did-nothing-wrong-martin-report-says }}</ref> The resulting "Martin Report" was published in February 2006 and found that Merck's senior management acted in good faith. The report attributed confusion over the clinical safety of Vioxx to the sales team's overzealous behavior.<ref name="Martin_report_2006">{{cite report |title=Report of the Honorable Judge John S. Martin Jr. to the Special Committee of the Board of Directors of Merck & Company, Inc concerning the conduct of senior management in the development and marketing of Vioxx |date=September 5, 2006 |work=Debevoise & Plimpton LLP | vauthors = Martin Jr JS | url=https://www.wsj.com/public/resources/documents/merck-report-20060906.pdf}}</ref> Merck was satisfied with the report findings and promised to consider its recommendations, while the press criticized its conclusions as self-serving.<ref name=nothing_wrong/>

==FDA position==
In 2005, American and Canadian advisory panels encouraged the return of rofecoxib to the market, stating that the drug's benefits outweighed the risks it posed to some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from [[ibuprofen]], while encouraging further study of all NSAIDs to fully understand their risk profiles. Despite this regulatory approval, Merck has not returned rofecoxib to the market.<ref>{{Cite news | url = https://www.news-medical.net/news/2005/07/11/11587.aspx | title = Vioxx safe enough for Canadian market says health panel | work = News-Medical.Net | date = 11 July 2005 | access-date = 27 March 2019 | archive-date = 27 March 2019 | archive-url = https://web.archive.org/web/20190327132023/https://www.news-medical.net/news/2005/07/11/11587.aspx | url-status = live }}</ref><ref>{{Cite news | url = https://money.cnn.com/2005/02/18/news/fortune500/merck/ | title = FDA panel: Vioxx can return to market | date = 18 February 2005 | agency = Reuters | via = CNN Money | access-date = 27 March 2019 | archive-date = 27 March 2019 | archive-url = https://web.archive.org/web/20190327133406/https://money.cnn.com/2005/02/18/news/fortune500/merck/ | url-status = live }}</ref>

Following the 2005 FDA Advisory Committee, the FDA issued a memo concluding that data from large long-term controlled clinical trials do not clearly demonstrate that COX-2 selective agents (including rofecoxib) have a greater risk of serious cardiovascular events than non-selective NSAIDs.<ref>{{Cite web|url=https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM106201.pdf|title=Analysis and recommendations for Agency action regarding nonsteroidal anti-inflammatory drugs and cardiovascular risk|website=FDA|access-date=2019-03-27|archive-date=2017-05-06|archive-url=https://web.archive.org/web/20170506134950/https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM106201.pdf}}</ref> In 2015, the FDA reinforced this conclusion, stating that the available data support a dose and duration-dependent effect on the risk of serious adverse cardiovascular events for COX-2 selective and non-selective NSAIDs.<ref name="fda.gov" />

==Litigation==
By March 2006, there were over 10,000 cases and 190 [[class action]]s filed against Merck<ref name="Petryna_Experiments_Travel_2009">{{cite book | title = ''When Experiments Travel:Clinical Trials and the Global Search for Human Subjects'' | vauthors = Petryna A | isbn = 978-0-691-12657-9 | date = 2009 | pages = 272 | publisher = [[Princeton University Press]] | url = https://books.google.com/books?id=cI6tAAAACAAJ | access-date = 2018-07-24 | archive-date = 2024-02-02 | archive-url = https://web.archive.org/web/20240202210958/https://books.google.com/books?id=cI6tAAAACAAJ | url-status = live }}</ref> over adverse cardiovascular events associated with rofecoxib and the adequacy of Merck's warnings. The first [[Wrongful death claim|wrongful death]] trial, ''Rogers v. Merck'', was scheduled in [[Alabama]] in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use.<ref>{{cite news|url=https://www.nytimes.com/2005/04/13/business/13drug.html?ex=1271044800&en=3225bb00e74eab08&ei=5090&partner=rssuserland|title=Merck Asks for a Dismissal in First of Suits Over Vioxx|newspaper=[[The New York Times]]|access-date=4 January 2015|vauthors=Berenson A|date=13 April 2005|archive-date=25 February 2012|archive-url=https://web.archive.org/web/20120225015434/http://www.nytimes.com/2005/04/13/business/13drug.html?ex=1271044800&en=3225bb00e74eab08&ei=5090&partner=rssuserland|url-status=live}}</ref>

On August 19, 2005, a jury in [[Texas]] voted 10–2 to hold Merck liable for the death of Robert Ernst, a 59-year-old man who allegedly died of a rofecoxib-induced heart attack. Merck argued that the death was due to [[cardiac arrhythmia]], which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award was capped at no more than US$26.1 million because of punitive damages limits under Texas law.<ref>{{cite web|url=http://www.nbcnews.com/id/9006921|title=Jury finds Merck liable in landmark Vioxx case|work=NBC News|date=20 August 2005|access-date=4 January 2015|archive-date=4 January 2015|archive-url=https://web.archive.org/web/20150104220315/http://www.nbcnews.com/id/9006921/}}</ref> Merck appealed and the verdict was overturned in 2008.<ref>{{cite web|url=http://www.chron.com/business/article/Houston-court-rejects-Vioxx-death-link-26-1-1770637.php|title=Houston court rejects Vioxx-death link, $26.1 million award|work=chron.com|access-date=28 September 2017|date=2008-05-29|archive-date=2017-09-29|archive-url=https://web.archive.org/web/20170929000625/http://www.chron.com/business/article/Houston-court-rejects-Vioxx-death-link-26-1-1770637.php|url-status=live}}</ref>
On November 3, 2005, Merck won the second case ''Humeston v. Merck'', a personal injury case, in [[Atlantic City, New Jersey|Atlantic City]], New Jersey. The plaintiff experienced a mild myocardial infarction and claimed that rofecoxib was responsible, after having taken it for two months. Merck argued that there was no evidence that rofecoxib was the cause of Humeston's injury and that there is no scientific evidence linking rofecoxib to cardiac events with short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug's risk.<ref>{{cite web | vauthors = Prakash S | date = 3 November 2005 | title = Jury Rules Merck Not Liable for Heart Attack Death | work = National Public Radio | url = https://www.npr.org/templates/story/story.php?storyId=4988532 | archive-url = https://web.archive.org/web/20150921162135/http://www.npr.org/templates/story/story.php?storyId=4988532| archive-date = September 21, 2015}}</ref>

The first federal trial on rofecoxib, ''Plunkett v. Merck'', began on November 29, 2005, in [[Houston]]. The trial ended on December 12, 2005, when Judge Eldon E. Fallon of U.S. District Court declared a mistrial because of a [[hung jury]] with an eight to one majority, favoring the defense. Upon retrial in February 2006 in [[New Orleans]], where the Vioxx [[multidistrict litigation]] (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the ''NEJM'' editor testify as to his objections to the VIGOR study.<ref name="NYT_Berenson_2005">{{citation |url=http://tech.mit.edu/V125/N61/61long4.html |title=Judge Declares Mistrial in Merck Vioxx Trial Because of Hung Jury |vauthors=Berenson A |work=The New York Times |date=December 13, 2005 |access-date=December 24, 2016 |archive-date=December 25, 2016 |archive-url=https://web.archive.org/web/20161225081817/http://tech.mit.edu/V125/N61/61long4.html }}</ref>

On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastrointestinal bleeding that he experienced after taking the drug. The judge said that Boyd failed to prove the drug caused his stomach pain and internal bleeding.

In January 2006, ''Garza v. Merck'' began trial in Rio Grande City, Texas. The plaintiff, a 71-year-old smoker with heart disease, had a fatal heart attack three weeks after finishing a one-week sample of rofecoxib. On April 21, 2006 the jury awarded the plaintiff $7 million compensatory and $25 million punitive. The [[Texas Courts of Appeals]] in San Antonio later ruled Garza's fatal heart attack probably resulted from pre-existing health conditions unrelated to his taking of Vioxx, thus reversing the $32 million jury award.<ref>{{cite news|url=https://www.bloomberg.com/apps/news?pid=20601087&sid=aVKMz77jAVo4&refer=home|title=Merck Wins Reversal of Jury's $32 Million Vioxx Award (Update3)|publisher=Bloomberg.com|access-date=4 January 2015|archive-date=2 February 2024|archive-url=https://web.archive.org/web/20240202210959/https://www.bloomberg.com/politics?pid=20601087&refer=home&sid=aVKMz77jAVo4|url-status=live}}</ref>

On April 5, 2006, a jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded McDarby $4.5 million in compensatory damages based on Merck's failure to properly warn of Vioxx safety risks. After a hearing on April 11, 2006, the jury also awarded Mr. McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial, but was liable for fraud in the sale of the drug to Cona.

In March 2010, an Australian class-action lawsuit against Merck ruled that Vioxx doubled the risk of heart attacks, and that Merck had breached the [[Trade Practices Act]] by selling a drug which was unfit for sale.<ref>{{cite news|url=http://www.theage.com.au/national/drug-unfit-for-sale-says-judge-in-compo-case-20100305-powh.html|title=Drug unfit for sale, says judge in compo case|work=The Age|access-date=4 January 2015|location=Melbourne|archive-date=24 October 2018|archive-url=https://web.archive.org/web/20181024192135/https://www.theage.com.au/national/drug-unfit-for-sale-says-judge-in-compo-case-20100305-powh.html|url-status=live}}</ref>

By November 2007 Merck announced that it agreed on a [[mass tort]] settlement of $4.85 billion between Merck and the lawyers of 27,000 individual lawsuits with a try-every-case strategy as opposed to a class action lawsuit if "85 percent of the plaintiffs sign up".<ref name="NYT_Merck_2007">{{cite news |title=Merck Agrees to Settle Vioxx Suits for $4.85 Billion |work=The New York Times |vauthors=Berensonnov A |date=November 9, 2007 |access-date=December 24, 2016 |url=https://www.nytimes.com/2007/11/09/business/09merck.html |archive-date=November 21, 2018 |archive-url=https://web.archive.org/web/20181121011945/https://www.nytimes.com/2007/11/09/business/09merck.html |url-status=live }}</ref><ref name="NYT_2008_Liptak">{{cite news |title=In Vioxx Settlement, Testing a Legal Ideal: A Lawyer's Loyalty |vauthors=Liptak A |date=January 22, 2008 |work=The New York Times |access-date=December 24, 2016 |url=https://www.nytimes.com/2008/01/22/us/22bar.html |archive-date=November 20, 2018 |archive-url=https://web.archive.org/web/20181120155347/https://www.nytimes.com/2008/01/22/us/22bar.html |url-status=live }}</ref> After the settlement, the lawyers for the case disputed the $315 million awarded in legal fees.<ref name="thenalfa.org">{{cite web|url=http://www.thenalfa.org/blog/$315m-fee-allocation-dispute-in-vioxx-class-action/|title=$315M Fee Allocation Dispure in Vioxx class actionThe NALFA|date=24 February 2011 |publisher=Thenalfa.org|access-date=4 January 2015|archive-date=5 January 2015|archive-url=https://web.archive.org/web/20150105010456/http://www.thenalfa.org/blog/$315m-fee-allocation-dispute-in-vioxx-class-action/|url-status=live}}</ref><ref>{{cite news|url=https://blogs.wsj.com/law/2011/03/03/the-vioxx-endgame-its-all-about-the-fees/|title=The Vioxx Endgame: It's All About the Fees|vauthors=Searcey D|work=WSJ|access-date=4 January 2015|date=3 March 2011|archive-date=24 October 2018|archive-url=https://web.archive.org/web/20181024113115/https://blogs.wsj.com/law/2011/03/03/the-vioxx-endgame-its-all-about-the-fees/|url-status=live}}</ref> Ultimately, the judge determined how the fees would be awarded to the plaintiff's attorneys.<ref>{{cite news|url=http://blogs.reuters.com/alison-frankel/2011/08/11/vioxx-judge-steps-in-to-split-350-ml-plaintiffs-lawyer-pie/|archive-url=https://web.archive.org/web/20111223210818/http://blogs.reuters.com/alison-frankel/2011/08/11/vioxx-judge-steps-in-to-split-350-ml-plaintiffs-lawyer-pie/|archive-date=23 December 2011|title=Vioxx judge steps in to split $350 ml plaintiffs lawyer pie|work=Reuters|access-date=4 January 2015|date=11 August 2011}}</ref> Judge [[Eldon E. Fallon]] of the [[United States District Court for the Eastern District of Louisiana]] additionally ordered the plaintiff lawyers to cap their fees at 32% of the settlement amount.<ref>{{cite web|url=http://www.laed.uscourts.gov/vioxx/|title=Vioxx Product Liability|publisher=Laed.uscourts.gov|access-date=4 January 2015|archive-date=5 January 2015|archive-url=https://web.archive.org/web/20150105005136/http://www.laed.uscourts.gov/vioxx/|url-status=live}}</ref>

The above dispute over lawyer fees has caused scholars and observers to consider tort reform throughout the country. Articles on the subject include ''The Vioxx Litigation: A Critical Look at Trial Tactics, the Tort System, and the Roles of Lawyers in Mass Tort Litigation''<ref name="McClellan_2008">{{cite journal | vauthors = McClellan F |title=The Vioxx Litigation: A Critical Look at Trial Tactics, the Tort System, and the Roles of Lawyers in Mass Tort Litigation |journal=DePaul Law Review |volume=57 |pages=509–38 |year=2008 |ssrn=1861337 }}</ref> and ''10 Years of Tort Reform in Texas Bring Fewer Suits, Lower Payouts.''<ref>{{cite web|url=http://www.insurancejournal.com/news/southcentral/2013/09/03/303718.htm|title=10 Years of Tort Reform in Texas Bring Fewer Suits, Lower Payouts|date=3 September 2013|publisher=Insurancejournal.com|access-date=4 January 2015|archive-date=3 December 2014|archive-url=https://web.archive.org/web/20141203022405/http://www.insurancejournal.com/news/southcentral/2013/09/03/303718.htm/|url-status=live}}</ref>

In November 2011, Merck announced a civil settlement with the [[US Attorney's Office for the District of Massachusetts]], and individually with 43 US states and the District of Columbia, to resolve civil claims relating to Vioxx.<ref>{{cite web | title = Merck Resolves Previously Disclosed Seven-Year Investigation Led by U.S. Attorney's Office for the District of Massachusetts Related to Vioxx® | date = 22 November 2011 | work = Merck & Co. | url = http://www.merck.com/newsroom/news-release-archive/corporate/2011_1122.html | archive-url = https://web.archive.org/web/20111124205736/http://www.merck.com/newsroom/news-release-archive/corporate/2011_1122.html| archive-date= 24 November 2011 }}</ref>  Under the terms of the settlement, Merck agreed to pay two-thirds of a previously recorded $950 million reserve charge in exchange for release from civil liability.  Litigation with seven additional states remains outstanding.  Under separate criminal proceedings, Merck pleaded guilty to a federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million.<ref>{{cite news|url=https://www.reuters.com/article/us-doj-merck-idUSTRE7AL2C120111122|title=Merck to pay $950 million to settle U.S. Vioxx charge|work=Reuters|access-date=4 January 2015|date=22 November 2011|archive-date=7 February 2016|archive-url=https://web.archive.org/web/20160207202215/http://www.reuters.com/article/us-doj-merck-idUSTRE7AL2C120111122|url-status=live}}</ref>

==Possible return to market==
In November 2017, Massachusetts-based [[Tremeau Pharmaceuticals]] announced its plan to return rofecoxib (TRM-201) to market as a treatment for [[hemophilic arthropathy]] (HA).  Tremeau announced that the FDA had granted an orphan designation for TRM-201 (rofecoxib) for the treatment of HA, and that they had received FDA feedback on their development plan.<ref name="Tremeau Pharmaceuticals News"/>  HA is a degenerative joint disease caused by recurrent intra-articular bleeding.  It is the largest cause of morbidity in patients with hemophilia and has no currently approved treatment options in the United States.  Traditional NSAIDs are avoided in this population due to their effects on platelet aggregation and risk of gastrointestinal ulcers,<ref name="Srivastava e1–e47"/> and high potency opioids are the current standard of care in treating HA.<ref name="Forsyth 1549"/>

In March 2019 Tremeau announced that they had hired as chief development officer a former Merck employee who had been a product development team leader and also was responsible for executive oversight for numerous clinical trials for the COX-2 inhibitor VIOXX (rofecoxib).  Tremeau also announced an upcoming clinical trial for rofecoxib and were seeking investigators.<ref>{{Cite web | url=https://www.tremeaurx.com/news/2019/3/8/tremeau-expands-leadership-team | title=Tremeau Expands Leadership Team | work=Tremeau Pharmaceuticals, Inc. | access-date=2020-02-18 | archive-date=2020-02-18 | archive-url=https://web.archive.org/web/20200218111126/https://www.tremeaurx.com/news/2019/3/8/tremeau-expands-leadership-team }}</ref><ref>{{Cite web | url=https://www.tremeaurx.com/news/2019/3/29/tremeau-to-exhibit-at-htrs-in-may | title=Tremeau to Exhibit at HTRS in May | work=Tremeau Pharmaceuticals, Inc. | access-date=2020-02-18 | archive-date=2020-02-18 | archive-url=https://web.archive.org/web/20200218111125/https://www.tremeaurx.com/news/2019/3/29/tremeau-to-exhibit-at-htrs-in-may }}</ref>

On February 15, 2022, California-based BriOri Biotech announced that it had been issued a patent covering topical formulations of rofecoxib.<ref>{{Cite news | url=https://www.bloomberg.com/press-releases/2022-02-15/briori-biotech-inc-granted-patent-for-topical-formulation-of-rofecoxib|title=BriOri BioTech Inc. Granted Patent for Topical Formulation of Rofecoxib |website=[[Bloomberg News]] |date=15 February 2022 | access-date=2022-09-15}}</ref>

== See also ==
* [[COX-2 selective inhibitor]]
* [[Discovery and development of cyclooxygenase 2 inhibitors]]
* [[David Graham (epidemiologist)]]

==Footnotes==
{{Reflist|colwidth=30em}}

== References ==
{{refbegin|30em}}
* {{cite web | work = FDA | title = Summary minutes for the February 16, 17 and 18, 2005, Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee. | date = March 2005 | url = https://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4090M1_Final.htm | access-date = 2019-12-16 | archive-date = 2017-05-10 | archive-url = https://web.archive.org/web/20170510083520/https://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4090M1_Final.htm }}
* {{cite journal | vauthors = Fitzgerald GA | title = Coxibs and cardiovascular disease | journal = The New England Journal of Medicine | volume = 351 | issue = 17 | pages = 1709–11 | date = October 2004 | pmid = 15470192 | doi = 10.1056/NEJMp048288 | doi-access = free }}
* {{cite web | vauthors = Grassley CE | date = 15 October 2004 | url = http://finance.senate.gov/press/Gpress/2004/prg101504.pdf | title = Grassley questions Merck about communication with the FDA on Vioxx | archive-url = https://web.archive.org/web/20041029135457/http://finance.senate.gov/press/Gpress/2004/prg101504.pdf | archive-date = 2004-10-29 }}
* {{cite journal | vauthors = Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M | title = Risk of cardiovascular events and rofecoxib: cumulative meta-analysis | journal = Lancet | volume = 364 | issue = 9450 | pages = 2021–9 | year = 2004 | pmid = 15582059 | doi = 10.1016/S0140-6736(04)17514-4 | s2cid = 9780851 }}
* {{cite journal | vauthors = Karha J, Topol EJ | title = The sad story of Vioxx, and what we should learn from it | journal = Cleveland Clinic Journal of Medicine | volume = 71 | issue = 12 | pages = 933–4, 936, 938–9 | date = December 2004 | pmid = 15641522 | doi = 10.3949/ccjm.71.12.933 | doi-broken-date = 31 July 2025 | s2cid = 19731479 }}
* {{cite journal | vauthors = Michaels D |date=June 2005 |title=Doubt is their Product |journal=Scientific American |volume=292 |issue=6 |pages=96–101 |doi=10.1038/scientificamerican0605-96 |pmid=15934658 |bibcode=2005SciAm.292f..96M }}
* {{cite web | publisher = Merck & Co. | date = 5 November 2004 | url = http://www.merck.com/statement_2004_1105/lancet.pdf | title = Response to Article by Juni et al. Published in The Lancet on Nov. 5. | work = Press Release | archive-url = https://web.archive.org/web/20041221215942/http://www.merck.com/statement_2004_1105/lancet.pdf | archive-date = 2004-12-21 }}
* {{cite web | publisher = Merck & Co | date = 30 September 2004 | title = Merck Announces Voluntary Worldwide Withdrawal of VIOXX. | work = Press release | url = http://vioxx.com/vioxx/documents/english/vioxx_press_release.pdf | archive-url = https://web.archive.org/web/20050118105613/http://vioxx.com/vioxx/documents/english/vioxx_press_release.pdf | archive-date = 2005-01-18 }}
* {{cite journal | vauthors = Mukherjee D, Nissen SE, Topol EJ | title = Risk of cardiovascular events associated with selective COX-2 inhibitors | journal = JAMA | volume = 286 | issue = 8 | pages = 954–9 | year = 2001 | pmid = 11509060 | doi = 10.1001/jama.286.8.954 | s2cid = 1117265 }}
* {{cite journal | vauthors = Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM | title = Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1081–91 | date = March 2005 | pmid = 15713945 | doi = 10.1056/NEJMoa050330 | s2cid = 27175006 | doi-access = free }}
* {{cite journal | vauthors = Okie S | title = Raising the safety bar--the FDA's coxib meeting | journal = The New England Journal of Medicine | volume = 352 | issue = 13 | pages = 1283–5 | date = March 2005 | pmid = 15800221 | doi = 10.1056/NEJMp058055 }}
* {{cite journal |doi=10.1016/j.tetlet.2004.12.055 |title=Facile air oxidation of the conjugate base of rofecoxib (Vioxx™), a possible contributor to chronic human toxicity |journal=Tetrahedron Letters |volume=46 |issue=6 |pages=927–929 |year=2005 | vauthors = Reddy LR, Corey EJ |doi-access=free }}
* {{cite journal | vauthors = Swan SK, Rudy DW, Lasseter KC, Ryan CF, Buechel KL, Lambrecht LJ, Pinto MB, Dilzer SC, Obrda O, Sundblad KJ, Gumbs CP, Ebel DL, Quan H, Larson PJ, Schwartz JI, Musliner TA, Gertz BJ, Brater DC, Yao SL | title = Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial | journal = Annals of Internal Medicine | volume = 133 | issue = 1 | pages = 1–9 | date = July 2000 | pmid = 10877734 | doi = 10.7326/0003-4819-133-1-200007040-00002 | s2cid = 41664773 }}
* {{cite web | vauthors = Targum SL | date = 1 February 2001 | title = Review of cardiovascular safety database. | work = FDA memorandum | url = https://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf | access-date = 16 December 2019 | archive-date = 27 January 2018 | archive-url = https://web.archive.org/web/20180127041414/https://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf }}
* {{cite journal | vauthors = Wolfe MM, Lichtenstein DR, Singh G | title = Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs | journal = The New England Journal of Medicine | volume = 340 | issue = 24 | pages = 1888–99 | date = June 1999 | pmid = 10369853 | doi = 10.1056/NEJM199906173402407 }}
* {{cite journal | title = Vioxx: an unequal partnership between safety and efficacy | journal = Lancet | volume = 364 | issue = 9442 | pages = 1287–8 | year = 2004 | pmid = 15474114 | doi = 10.1016/S0140-6736(04)17198-5 | last1 = The Lancet | s2cid = 29472727 | doi-access = free }}
{{refend}}

== External links ==

* [https://web.archive.org/web/20070103071954/http://www.courttv.com/trials/vioxx/ Court TV's full coverage of the Vioxx civil trials]
* [https://web.archive.org/web/20060822003656/http://www.learnaboutvioxx.com/ Merck website on Vioxx litigation]


{{Anti-inflammatory and antirheumatic products}}
{{Analgesics}}
{{Prostanoidergics}}
{{Merck&Co}}

[[Category:Withdrawn drugs]]
[[Category:Drugs developed by Merck & Co.]]
[[Category:Nonsteroidal anti-inflammatory drugs]]
[[Category:Cyclooxygenase-2 inhibitors]]
[[Category:Benzosulfones]]
[[Category:Furanones]]