Rofecoxib

Rofecoxib /ˌrɒfɪˈkɒksɪb/ is a nonsteroidal anti-inflammatory drug (NSAID) that has

Rofecoxib
now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat
osteoarthritis, acute pain conditions, and dysmenorrhea. Rofecoxib was approved by
the U.S. Food and Drug Administration (FDA) on May 20, 1999, and was marketed
under the brand names Vioxx, Ceoxx, and Ceeoxx.

Rofecoxib gained widespread acceptance among physicians treating patients with

arthritis and other conditions causing chronic or acute pain. Worldwide, over 80
[1]
million people were prescribed rofecoxib at some time.

On September 30, 2004, Merck withdrew rofecoxib from the market because of
concerns about increased risk of 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,
resulting in between 88,000 and 140,000 cases of serious heart disease.[2] Rofecoxib
was one of the most widely used drugs ever to be withdrawn from the market. In the Clinical data
year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[3] Pregnancy AU: C
Merck reserved $970 million to pay for its Vioxx-related legal expenses through category
2007, and has set aside $4.85bn for legal claims from US citizens. Routes of oral & i.m
administration
Rofecoxib was available on prescription in both tablet-form and as an oral ATC code M01AH02 (WHO)
suspension. It was available by injection for hospital use.
Legal status
Legal status withdrawn
worldwide

Contents Pharmacokinetic data

Bioavailability 93%
Mode of action
Pharmacokinetics Protein binding 87%
Fabricated efficacy studies
Metabolism hepatic
Side effects
Biological half- 17 hours
Heart and blood vessels
life
VIGOR study and publishing controversy
Alzheimer's disease
Excretion biliary/renal
Premenstrual acne Identifiers
APPROVe study
IUPAC name
Other studies
Other COX-2 inhibitors CAS Number 162011-90-7
Other NSAIDs
PubChem CID 5090
Withdrawal
The Martin Report 2006
IUPHAR/BPS 2893
Litigation DrugBank DB00533
Possible return to market ChemSpider 4911
See also
UNII 0QTW8Z7MCR
Footnotes
References KEGG D00568
External links
 ChEBI CHEBI:8887
ChEMBL CHEMBL122
Mode of action ECHA InfoCard 100.230.077
Cyclooxygenase (COX) has two well-studied isoforms, called COX-1 and COX-2. Chemical and physical data
COX-1 mediates the synthesis of prostaglandins responsible for protection of the
Formula C17H14O4S
stomach lining, while COX-2 mediates the synthesis of prostaglandins responsible
for pain and inflammation. By creating "selective" NSAIDs that inhibit COX-2, but
Molar mass 314.357 g/mol
not COX-1, the same pain relief as traditional NSAIDs is offered, but with greatly 3D model Interactive image
reduced risk of fatal or debilitating peptic ulcers. Rofecoxib is a selective COX-2
(JSmol)
inhibitor, or "coxib". SMILES
InChI
Others include Merck's etoricoxib (Arcoxia), Pfizer’s celecoxib (Celebrex) and
valdecoxib (Bextra). Interestingly, at the time of its withdrawal, rofecoxib was the (verify)
only coxib 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 andnaproxen.[4]

Pharmacokinetics
The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%.[5][6][7] Rofecoxib
crossed the placenta and blood–brain barrier,[5][6][8] and took 1–3 hours to reach peak plasma concentration with an effective half-life
[5][7][9] The metabolic products are cis-dihydro and trans-dihydro derivatives
(based on steady-state levels) of approximately 17 hours.
of rofecoxib[5][9] which are primarily excreted through urine.

Fabricated efficacy studies

On March 11, 2009, 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 in order to augment
the analgesic effects of the drugs. There is no evidence 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 manufacturerMerck had no comment on the disclosure.[10][11]

Side effects
Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse fect
ef profile to other
NSAIDs.

Prostaglandin is a large family of lipids. Prostaglandin I2/PGI2/prostacyclin is just one member of it.
Prostaglandins other than PGI2 (such as PGE2) also play important roles in vascular tone regulation.
Prostacyclin/thromboxane are produced by both COX-1 and COX-2, and rofecoxib suppresses just COX-2
enzyme, so there is no reason to believe that prostacyclin levels are significantly reduced by the drug. And there
is no reason to believe that only the balance between quantities of prostacyclin and thromboxane is the
determinant factor for vascular tone.[12] Indeed, Merck has stated that there was no effect on prostacyclin production in blood vessels
in animal testing.[13] Corey speculated that the cardiotoxicity may be associated with an organic acid anhydride formed when
rofecoxib is exposed to air.[14]

Heart and blood vessels

VIGOR study and publishing controversy
The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., which compared the efficacy and adverse effect
profiles of rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in
rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12-month span of the study. The
elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular
events between the two groups, nor was there any significant difference in the rate of myocardial infarction between the rofecoxib
and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at
higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events
(previous myocardial infarction, angina,cerebrovascular accident, transient ischemic attack, or coronary artery bypass).

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.[15] Some commentators have noted that naproxen would have to be three times as effective as
aspirin to account for all of the difference,[16] and some outside scientists warned Merck that this claim was implausible before
VIGOR was published.[17] 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.[18][19]

The results of the VIGOR study were submitted to the United States Food and Drug Administration (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 non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)."[20] 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, 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.[21] 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
[22]
actually used in the December trial, Curfman had testified well before the publication of the editorial.

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 (2-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
[23]
publicly in March 2000, eight months before publication.

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 and thus were appropriately not included. (Utilizing 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.[24]

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).[23]
Some scientists have accused the NEJM editorial board of making unfounded accusations.[25][26] Others have applauded the
editorial. Renowned research cardiologistEric Topol,[27] a prominent Merck critic, accused Merck of "manipulation of data" and said
[28] Phil Fontanarosa, executive editor of the prestigiousJournal
"I think now the scientific misconduct trial is really fully backed up".
of the American Medical Association, welcomed the editorial, saying "this is another in the long list of recent examples that have
[29]
generated real concerns about trust and confidence in industry-sponsored studies".

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 theNew England Journal of Medicine's own role in aiding Vioxx sales."[30]

"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."[30] 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.[31][32][33]

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 due to
rofecoxib.[34] Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib's safety
.

Premenstrual acne
A 2003 placebo-controlled small short-term study in India of 80 women with premenstrual acne vulgaris acne, were given rofecoxib
fective in the management of premenstrual acne.[35]
or placebo for 2 cycles of 10 days suggest that "rofecoxib is ef

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 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.

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.[36]

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
Pre-approval Phase IIIclinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for
the first eighteen months of rofecoxib usage (Merck, 2004). Others have pointed out that "study 090," a pre-approval trial, showed a
3-fold increase in cardiovascular events compared to placebo, a 7-fold increase compared to nabumetone (another [NSAID]), and an
8-fold increase in heart attacks and strokes combined compared to both control groups.[15][37] 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.[38]

Other COX-2 inhibitors

Any increased risk of renal and arrhythmia pathologies associated with the class of COX-2 inhibitors, e.g. celecoxib (Celebrex),
valdecoxib (Bextra), parecoxib (Dynastat), lumiracoxib, and etoricoxib is not evident,[38] although smaller studies[39][40] had
demonstrated such effects earlier with the use of celecoxib, valdecoxib and parecoxib.

Nevertheless, it is likely that trials of newer drugs in the category will be extended in order to supply additional evidence of
cardiovascular safety. Examples are some more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige),
which are currently (circa 2005) undergoing Phase III/IV clinical trials.

Besides, 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:[41]

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 possibleduration 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 sort 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 due to their
anti-platelet aggregation properties.

Withdrawal
Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market
worldwide on September 30, 2004.[42][43]
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). FDA analysts estimated that
Vioxx 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.[44]

On November 5, 2004, the medical journal The Lancet published a meta-analysis of the available studies on the safety of
rofecoxib[45] (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.[46][47] 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. (Merck & Co., 2004).

In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib's
benefits outweighed the risks for 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—though the panel stated that further study was needed for all
NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the
market.[48]

The Martin Report 2006

In 2005, Merck retained John S. Martin Jr., a former US District Judge for the Southern District of New York and colleagues at
Debevoise & Plimpton LLP to investigate Vioxx study results and communications conducted by Merck. Through the report, it was
found that Merck's senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the
sales team's overzealous behavior. The report that was filed gave a timeline of the events surrounding Vioxx and showed that Merck
intended to operate honestly throughout the process. Any mistakes that were made regarding the mishandling of clinical trial results
and withholding of information was the result of oversight, not malicious behavior. The Martin Report did conclude that the Merck's
marketing team exaggerated the safety of Vioxx and replaced truthful information with sales tactics. The report was published in
February 2006, and Merck was satisfied with the findings of the report and promised to consider the recommendations contained in
the Martin Report.[49]

Litigation
By March 2006, there were over 10,000 cases and 190 class actions filed against Merck[50] over adverse cardiovascular events
associated with rofecoxib and the adequacy of Merck's warnings. The first wrongful death trial, Rogers v. Merck, was scheduled in
gued that the plaintiff had falsified evidence of rofecoxib use.[51]
Alabama in the spring of 2005, but was postponed after Merck ar

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. The plaintiff's lead attorney was Mark Lanier. 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.[52] Merck appealed and the verdict was overturned in 2008.[53] On November 3, 2005, Merck won the second case
Humeston v. Merck, a personal injury case, in 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
[54]
use. The jury ruled that Merck had adequately warned doctors and patients of the drug's risk.

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
.[55]
found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study
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 state court of appeals in San Antonio later ruled Garza's fatal heart attack
V thus reversing the $32 million jury award.[56]
probably resulted from pre-existing health conditions unrelated to his taking of ioxx,

On April 5, 2006, the jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded Mr 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.[57]

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 straegy as opposed to a class action lawsuit if "85 percent of the plaintiffs sign
up."[58][59] After the settlement, the lawyers for the case disputed the $315 million awarded in legal fees.
[60][61] Ultimately, the judge

determined how the fees would be awarded to the plaintiff’s attorneys.[62] Judge Eldon E. Fallon of the United States District Court
for the District of Orleansadditionally ordered the plaintiff lawyers to cap their fees at 32% of the settlement amount.[63]

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[64] and 10 Years of Tort Reform in Texas Bring Fewer Suits, Lower Payouts.[65]

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.[66] 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
[67]
federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million.

Possible return to market

In November 2017, Cambridge, Mass.-based Tremeau Pharmaceuticals announced its plan to return rofecoxib to market as a
treatment for severe joint pain caused by hemophilia.[12] Unlike NSAIDS, rofecoxib is unlikely to cause internal bleeding, nor does
it carry the higher risk of addiction that opioids do.

See also
COX-2 selective inhibitor
Discovery and development of cyclooxygenase 2 inhibitors

Footnotes
1. Knox, Richard (September 30, 2004),Merck Pulls Arthritis Drug Vioxx from Market (https://web.archive.org/web/201
01111103315/http://www.npr.org/templates/story/story.php?storyId=4054991), archived from the original (http://www.
npr.org/templates/story/story.php?storyId=4054991)on November 11, 2010, retrieved December 24, 2016
2. "Up to 140,000 heart attacks linked to Vioxx" (https://www.newscientist.com/article/dn6918-up-to-140000-heart-attac
ks-linked-to-vioxx.html). New Scientist. 2005-01-25. p. 1.
 3. "Merck Sees Slightly Higher 2007 Earnings"(https://www.nytimes.com/2006/12/07/business/07drug.html?ex=13231
47600&en=19d27b5814f1c1e8&ei=5088&partner=rssnyt&emc=rss) . New York Times. Reuters. 2006-12-07. p.A1.
4. Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M. B.; Hawkey, C.
J.; Hochberg, M. C.; Kvien, T. K.; Schnitzer, T. J.; Vigor Study, G. (2000). "Comparison of Upper Gastrointestinal
Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis".New England Journal of Medicine. 343
(21): 1520–1528, 2 1528 following 1528.doi:10.1056/NEJM200011233432103(https://doi.org/10.1056%2FNEJM20
0011233432103). PMID 11087881 (https://www.ncbi.nlm.nih.gov/pubmed/11087881).
5. "VIOXX® (rofecoxib tablets and oral suspension) : DESCRIPTION"(http://www.merck.com/product/usa/pi_circulars/
v/vioxx/vioxx_pi.pdf) (PDF). Merck.com. Retrieved 4 January 2015.
6. "MD Consult - Important Notice"(http://www.mdconsult.com/das/pharm/body/181267313-3/946823742/full/2399).
Mdconsult.com. Retrieved 4 January 2015.
7. Davies, N. M.; Teng, X. W.; Skjodt, N. M. (2003). "Pharmacokinetics of rofecoxib: a specifi
c cyclo-oxygenase-2
inhibitor". Clinical pharmacokinetics. 42 (6): 545–556. doi:10.2165/00003088-200342060-00004(https://doi.org/10.2
165%2F00003088-200342060-00004). PMID 12793839 (https://www.ncbi.nlm.nih.gov/pubmed/12793839).
8. Padi, S.; Kulkarni, S. (2004). "Differential effects of naproxen and rofecoxib on the develop
ment of hypersensitivity
following nerve injury in rats".Pharmacology Biochemistry and Behavior. 79 (2): 349–358.
doi:10.1016/j.pbb.2004.08.005(https://doi.org/10.1016%2Fj.pbb.2004.08.005) . PMID 15501312 (https://www.ncbi.nl
m.nih.gov/pubmed/15501312).
9. Scott, L. J.; Lamb, H. M. (1999). "Rofecoxib".Drugs. 58 (3): 499–505; discussion 506–7.doi:10.2165/00003495-
199958030-00016 (https://doi.org/10.2165%2F00003495-199958030-00016) . PMID 10493277 (https://www.ncbi.nl
m.nih.gov/pubmed/10493277).
10. Winstein, Keith J. (March 11, 2009)."Top Pain Scientist Fabricated Data in Studies, Hospital Says" (https://www.wsj.
com/articles/SB123672510903888207?mod=loomia&loomia_si=t0:a16:g2:r1:c0.0270612:b22894832) . The Wall
Street Journal.
11. Anna Wilde Mathews and Barbara Martinez (November 1, 2004),E-Mails Suggest Merck Knew Vioxx's Dangers at
Early Stage As Heart-Risk Evidence Rose: Officials Played Hardball; Internal Message: 'Dodge!'
(https://www.wsj.co
m/articles/SB109926864290160719), Wall Street Journal
12. Vane, J.; Bakhle, Y.; Botting, R. (1998). "Cyclooxygenases 1 and 2".Annual Review of Pharmacology and
Toxicology. 38: 97–120. doi:10.1146/annurev.pharmtox.38.1.97 (https://doi.org/10.1146%2Fannurev.pharmtox.38.1.9
7). PMID 9597150 (https://www.ncbi.nlm.nih.gov/pubmed/9597150).
13. [1] (http://www.sfgate.com/cgi-bin/article.cgi?f=/n/a/2006/02/14/financial/f124814S66.DTL&type=health)Archived (htt
ps://web.archive.org/web/20081029024523/http://www .sfgate.com/cgi-bin/article.cgi?f=%2Fn%2Fa%2F2006%2F0
2%2F14%2Ffinancial%2Ff124814S66.DTL&type=health)October 29, 2008, at theWayback Machine.
14. http://cen.acs.org/articles/83/i2/Investigating-V
ioxx-Toxicity.html
15. "NAME OF DRUG: Rofecoxib (MK-0966) : Memorandum"(http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_
06_cardio.pdf) (PDF). Fda.gov. Retrieved 4 January 2015.
16. [2] (http://www.powerlinefacts.com/Sciam_article_on_lobbying.htm) Archived (https://web.archive.org/web/20150104
200843/http://www.powerlinefacts.com/Sciam_article_on_lobbying.htm)January 4, 2015, at theWayback Machine.
17. [3] (http://www.saferdrugsnow.org/documents/vio/E-mailreCarloPatronoVIGOR.pdf)Archived (https://web.archive.or
g/web/20060625011642/http://www.saferdrugsnow.org/documents/vio/E-mailreCarloPatronoVIGOR.pdf)June 25,
2006, at the Wayback Machine.
18. Karha, J.; Topol, E. J. (2004). "The sad storyof Vioxx, and what we should learn from it".Cleveland Clinic journal of
medicine. 71 (12): 933–934, 936, 934–9.doi:10.3949/ccjm.71.12.933(https://doi.org/10.3949%2Fccjm.71.12.933).
PMID 15641522 (https://www.ncbi.nlm.nih.gov/pubmed/15641522).
19. Solomon, D. H.; Glynn, R. J.; Levin, R.; Avorn, J. (2002). "Nonsteroidal anti-inflammatory drug use and acute
myocardial infarction".Archives of Internal Medicine. 162 (10): 1099–1104. doi:10.1001/archinte.162.10.1099(http
s://doi.org/10.1001%2Farchinte.162.10.1099). PMID 12020178 (https://www.ncbi.nlm.nih.gov/pubmed/12020178).
20. "Warning Letter" (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActi
vitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM 166383.pdf) (PDF).
Fda.gov. Retrieved 4 January 2015.
21. Curfman, G.; Morrissey, S.; Drazen, J. (2005). "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". The New England Journal of Medicine. 353 (26): 2813–2814. doi:10.1056/NEJMe058314(https://
doi.org/10.1056%2FNEJMe058314). PMID 16339408 (https://www.ncbi.nlm.nih.gov/pubmed/16339408).
22. [4] (https://www.forbes.com/work/feeds/ap/2006/02/13/ap2523250.html)
23. Curfman, G.; Morrissey, S.; Drazen, J. (2006). "Expression of concern reaffirmed". The New England Journal of
Medicine. 354 (11): 1193. doi:10.1056/NEJMe068054(https://doi.org/10.1056%2FNEJMe068054). PMID 16495386
(https://www.ncbi.nlm.nih.gov/pubmed/16495386).
24. Bombardier, Claire; Laine, L.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M.; Hawkey, C.; Hochberg, M.; Kvien,
T.; Schnitzer, T. J.; Weaver, A. (2006). "Response to expression of concern regarding VIGOR study".The New
England Journal of Medicine. 354 (11): 1196–1199. doi:10.1056/NEJMc066096(https://doi.org/10.1056%2FNEJMc0
66096). PMID 16495387 (https://www.ncbi.nlm.nih.gov/pubmed/16495387).
25. Lowe, Derek. "NEJM vs. Its Contributors, Round Two" (http://blogs.sciencemag.org/pipeline/archives/2006/02/22/nej
m_vs_its_contributors_round_two/). Science. Retrieved 20 November 2015.
26. [5] (http://dimer.tamu.edu/simplog/archive.php?blogid=3&pid=3293) Archived (https://web.archive.org/web/20120610
235819/http://dimer.tamu.edu/simplog/archive.php?blogid=3&pid=3293)June 10, 2012, at the Wayback Machine.
27. [6] (http://genetics.case.edu/faculty2.php?fac=ejt9)Archived (https://web.archive.org/web/20060908042122/http://ge
netics.case.edu/faculty2.php?fac=ejt9)September 8, 2006, at theWayback Machine.
28. [7] (http://www.medicinenet.com/script/main/art.asp?articlekey=56384&page=2)
29. "Vioxx Plaintiffs seek Mistrial after Allegation on Merck Study"(http://www.beasleyallen.com/news/vioxx-plaintiffs-see
k-mistrial-after-allegation-on-merck-study/). Beasleyallen.com. Retrieved 4 January 2015.
30. David Armstrong (2006-05-15)."How the New England Journal Missed Warning Signs on Vioxx" (https://www.wsj.co
m/articles/SB114765430315252591). Wall Street Journal. p. A1.
31. https://www.nytimes.com/2005/04/24/business/evidence-in-vioxx-suits-shows-intervention-by-merck-of
ficials.html
32. https://blogs.wsj.com/law/2006/02/08/the-merck-trial-edward-the-scalder-scolnick/
33. https://web.duke.edu/kenanethics/CaseStudies/V
ioxx.pdf
34. Konstam, M. A.; Weir, M. R.; Reicin, A.; Shapiro, D.; Sperling, R. S.; Barr , E.; Gertz, B. J. (2001). "Cardiovascular
thrombotic events in controlled, clinical trials of rofecoxib".Circulation. 104 (19): 2280–2288.
doi:10.1161/hc4401.100078(https://doi.org/10.1161%2Fhc4401.100078). PMID 11696466 (https://www.ncbi.nlm.ni
h.gov/pubmed/11696466).
35. [8] (https://tspace.library.utoronto.ca/handle/1807/3834)
36. Bresalier, R.; Sandler, R.; Quan, H.; Bolognese, J.; Oxenius, B.; Horgan, K.; Lines, C.; Rid
dell, R.; Morton, D.; Lanas,
A.; Konstam, M. A.; Baron, J. A.; Adenomatous Polyp Prevention on ioxxV (APPROVe) Trial Investigators (2005).
"Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial". The New England
Journal of Medicine. 352 (11): 1092–1102. doi:10.1056/NEJMoa050493(https://doi.org/10.1056%2FNEJMoa05049
3). PMID 15713943 (https://www.ncbi.nlm.nih.gov/pubmed/15713943).
37. Wolfe, M. M. (2004). "Rofecoxib, Merck, andthe FDA". The New England Journal of Medicine. 351 (27): 2875–2878;
author 2878 2875–2878.doi:10.1056/NEJM200412303512719(https://doi.org/10.1056%2FNEJM20041230351271
9). PMID 15625749 (https://www.ncbi.nlm.nih.gov/pubmed/15625749).
38. Zhang, J.; Ding, E.; Song, Y. (2006). "Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events:
meta-analysis of randomized trials".Journal of the American Medical Association. 296 (13): 1619–1632.
doi:10.1001/jama.296.13.jrv60015(https://doi.org/10.1001%2Fjama.296.13.jrv60015) . PMID 16968832 (https://www.
ncbi.nlm.nih.gov/pubmed/16968832).
39. Solomon, S.; McMurray, J.; Pfeffer, M.; Wittes, J.; Fowler, R.; Finn, P.; Anderson, W.; Zauber, A.; Hawk, E.;
Bertagnolli, M.; Adenoma Prevention with Celecoxib (APC) Study Investigators (2005). "Cardiovascular risk
associated with celecoxib in a clinical trial for colorectal adenoma prevention".The New England Journal of
Medicine. 352 (11): 1071–1080. doi:10.1056/NEJMoa050405(https://doi.org/10.1056%2FNEJMoa050405).
PMID 15713944 (https://www.ncbi.nlm.nih.gov/pubmed/15713944).
40. Nussmeier, N.; Whelton, A.; Brown, M.; Langford, R.; Hoeft, A.; Parlow, J.; Boyce, S.; Verburg, K. (2005).
"Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery". The New England Journal of
Medicine. 352 (11): 1081–1091. doi:10.1056/NEJMoa050330(https://doi.org/10.1056%2FNEJMoa050330).
PMID 15713945 (https://www.ncbi.nlm.nih.gov/pubmed/15713945).
41. "European Medicines Agency concludes action on COX-2 inhibitors"(http://www.emea.europa.eu/pdfs/human/press/
pr/20776605en.pdf) (pdf). European Medicines Agency. Retrieved 2008-04-16.
42. "Merck Announces Voluntary Worldwide Withdrawal of VIOXX"(https://web.archive.org/web/20120417053059/http://
www.merck.com/newsroom/vioxx/pdf/vioxx_press_release_final.pdf)(PDF). Merck.com. Archived fromthe original (h
ttp://www.merck.com/newsroom/vioxx/pdf/vioxx_press_release_final.pdf)(pdf) on 17 April 2012. Retrieved 4 January
2015.
43. "Q&A on the case, following withdrawal announcement"(http://www.npr.org/templates/story/story.php?storyId=40549
91), National Public Radio (NPR), 2004, retrieved December 24, 2016
44. "Congress Questions Vioxx, FDA" (https://www.pbs.org/newshour/bb/health/july-dec04/vioxx_11-18.html). PBS
NewsHour. 2004-11-18. Retrieved 2013-06-03.
45. Peter Jüni, Linda Nartey, Stephan Reichenbach, Rebekka Sterchi, Paul A Dieppe, Matthias Egger (December 4,
2004). "Risk of cardiovascular events and rofecoxib: cumulative meta-analysis"
(https://web.archive.org/web/201604
29083940/http://vioxxnationalclassaction.ca/Press/2004_11_06_Lancet.pdf) (PDF). The Lancet. 364 (9450): 2021–
2029. doi:10.1016/S0140-6736(04)17514-4(https://doi.org/10.1016%2FS0140-6736%2804%2917514-4) . Archived
from the original (http://vioxxnationalclassaction.ca/Press/2004_11_06_Lancet.pdf)(PDF) on April 2016. Retrieved
December 24, 2016.
46. [9] (http://thelancet.com/journal/vol364/iss9446/full/llan.364.9446.early_online_publication.31178.1)
47. Horton, Richard (December 2004). "Vioxx, the Implosion of Merck, and Aftershocks at the FDA".The Lancet. 364
(9450): 1995–1996. doi:10.1016/S0140-6736(04)17523-5(https://doi.org/10.1016%2FS0140-6736%2804%2917523
-5).
48. "SUMMARY: Report of the Expert Advisory Panel on the Safety of Cox-2 Selective Non-steroidal Anti-Inflammatory
Drugs (NSAIDs)" (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/sci-consult/cox2/sap_summary_gcs_sommair
e_cox2_e.html). Health Canada. 2005-07-06. Retrieved 2011-06-04.
49. John S. Martin Jr. (September 5, 2006). Report of the Honorable JudgeJohn 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. Debevoise & Plimpton LLP(Report). p. 183.
50. Petryna, Adriana (2009). When Experiments T ravel:Clinical Trials and the Global Search for Human Subjects.
Princeton University Press. p. 272. ISBN 9780691126579.
51. Berenson, Alex (13 April 2005)."Merck Asks for a Dismissal in First of Suits Over V
ioxx" (https://www.nytimes.com/2
005/04/13/business/13drug.html?ex=1271044800&en=3225bb00e74eab08&ei=5090&partner=rssuserland) . The
New York Times. Retrieved 4 January 2015.
52. "Jury finds Merck liable in landmark Vioxx case" (http://www.msnbc.msn.com/id/9006921/). msnbc.com. Retrieved
4 January 2015.
53. "Houston court rejects Vioxx-death link, $26.1 million award" (http://www.chron.com/business/article/Houston-court-r
ejects-Vioxx-death-link-26-1-1770637.php). chron.com. Retrieved 28 September 2017.
54. [10] (http://www.npr.org/templates/story/story.php?storyId=4988532) Archived (https://web.archive.org/web/2015092
1162135/http://www.npr.org/templates/story/story.php?storyId=4988532)September 21, 2015, at theWayback
Machine.
55. Berenson, Alex (December 13, 2005),Judge Declares Mistrial in Merck Vioxx Trial Because of Hung Jury(http://tec
h.mit.edu/V125/N61/61long4.html), The New York Times, retrieved December 24, 2016
56. "Merck Wins Reversal of Jury's $32 Million V
ioxx Award (Update3)" (https://www.bloomberg.com/apps/news?pid=20
601087&sid=aVKMz77jAVo4&refer=home). Bloomberg.com. Retrieved 4 January 2015.
57. "Drug unfit for sale, says judge in compo case"(http://www.theage.com.au/national/drug-unfit-for-sale-says-judge-in-
compo-case-20100305-powh.html). The Age. Melbourne. Retrieved 4 January 2015.
58. Berensonnov, Alex (November 9, 2007)."Merck Agrees to Settle Vioxx Suits for $4.85 Billion" (https://www.nytimes.c
om/2007/11/09/business/09merck.html). The New York Times. Retrieved December 24, 2016.
59. Liptak, Adam (January 22, 2008)."In Vioxx Settlement, Testing a Legal Ideal: A Lawyer's Loyalty"(https://www.nytim
es.com/2008/01/22/us/22bar.html). The New York Times. Retrieved December 24, 2016.
60. "$315M Fee Allocation Dispure in Vioxx class actionThe NALFA" (http://www.thenalfa.org/blog/$315m-fee-allocation-
dispute-in-vioxx-class-action/). Thenalfa.org. Retrieved 4 January 2015.
61. Dionne Searcey (3 March 2011)."The Vioxx Endgame: It's All About the Fees"(https://blogs.wsj.com/law/2011/03/0
3/the-vioxx-endgame-its-all-about-the-fees/). WSJ. Retrieved 4 January 2015.
62. "Vioxx judge steps in to split $350 ml plaintiffs lawyer pie" (http://blogs.reuters.com/alison-frankel/2011/08/11/vioxx-ju
dge-steps-in-to-split-350-ml-plaintiffs-lawyer-pie/). Reuters. 11 August 2011. Retrieved 4 January 2015.
63. "Vioxx Product Liability" (http://www.laed.uscourts.gov/vioxx/). Laed.uscourts.gov. Retrieved 4 January 2015.
64. McClellan, Frank (2008). "The Vioxx Litigation: A Critical Look at Trial Tactics, the Tort System, and the Roles of
Lawyers in Mass Tort Litigation". DePaul Law Review. 57: 509–538.
65. "10 Years of Tort Reform in Texas Bring Fewer Suits, Lower Payouts"(http://www.insurancejournal.com/news/southc
entral/2013/09/03/303718.htm). Insurancejournal.com. 3 September 2013. Retrieved 4 January 2015.
66. [11] (http://www.merck.com/newsroom/news-release-archive/corporate/2011_1122.html)Archived (https://web.archiv
e.org/web/20111124205736/http://www.merck.com/newsroom/news-release-archive/corporate/2011_1122.html)
November 24, 2011, at theWayback Machine.
67. "Merck to pay $950 million to settle U.S. Vioxx charge" (https://www.reuters.com/article/2011/11/22/us-doj-merck-idU
STRE7AL2C120111122). Reuters. 22 November 2011. Retrieved 4 January 2015.

References
FDA (2005). "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." Published on the internet, March 2005.
Link
Fitzgerald GA, Coxibs and Cardiovascular Disease,N Engl J Med 2004;351(17): 1709–1711. PMID 15470192.
Grassley CE (15 Oct 2004).Grassley questions Merck about communication with the FDA on iV oxx. Press Release.
Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe P A, Egger M (2004). Risk of cardiovascular events and
rofecoxib: cumulative meta-analysis.Lancet (published online; see also Merck response below)
Karha J and Topol EJ. The sad story of Vioxx, and what we should el arn from it Cleve Clin J Med 2004; 71(12):933-
939. PMID 15641522
Michaels, D. (June 2005)DOUBT Is Their Product, Scientific American, 292 (6).
Merck & Co., (5 Nov 2004).Response to Article by Juni et al. Published in The Lancet on Nov . 5. Press Release.
Merck & Co (30 Sep 2004) Merck Announces V oluntary Worldwide Withdrawal of VIOXX. Press release[13].
D. M. Mukherjee, S. E. Nissen, and E. J. T opol, "Risk of Cardiovascular Events Associated with Selective COX-2
Inhibitors," Journal of the American Medical Association 186 (2001): 954–959.
Nussmeier NA, Whelton AA, Brown MT , Langford RM, Hoeft A, Parlow JL,et al. Complications of the COX-2
inhibitors parecoxib and valdecoxib after cardiac surgery . N Engl J Med 2005;352(11):1081-91. PMID 15713945
Okie, S (2005) "Raising the safety bar--the FDA's coxib meeting."N Engl J Med. 2005 Mar 31;352(13):1283-5.
PMID 15800221.
Leleti Rajender Reddy, Corey EJ. Facile air oxidation of the conjugate base of rofecoxib (V ioxx), a possible
contributor to chronic human toxicityTetrahedron Lett 2005, 46: 927. doi:10.1016/j.tetlet.2004.12.055
Swan SK et al., Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt
Diet. Annals of Int Med 2000; 133:1–9
Targum, SL. (1 Feb. 2001) Review of cardiovascular safety database.FDA memorandum. [14]
Wolfe, MM et al., Gastrointestinal Toxicity of Nonsteroidal Anti-anflamattory Drugs, New England Journal of
Medicine. 1999; 340; 1888-98.

External links
Court TV's full coverage of the Vioxx civil trials
Merck website on Vioxx litigation
FDA Public Health Advisory on Vioxx
David Michaels. Doubt is Their ProductScientific American, June 2004, p. 96-101
JURIST, Much Pain, Much Gain: Skeptical Ruminations on the V ioxx Litigation
Ted Frank, American Enterprise Institute, The Vioxx Litigation, Part I and Part II, December 2005
briandeer.com - Vioxx: the UK connection
Campaign for compensation for Vioxx victims outside the US

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