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Rofecoxib
Clinical data
Pronunciation/ˌrɒfɪˈkɒksɪb/
Trade namesVioxx, Ceoxx, Ceeoxx, others
Pregnancy
category
  • AU: C
Routes of
administration		By mouth & i.m
ATC code
Legal status
Legal status
  • withdrawn worldwide
Pharmacokinetic data
Bioavailability93%
Protein binding87%
Metabolismliver
Elimination half-life17 hours
Excretionbile duct/kidney
Identifiers
  • 4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.230.077 Edit this at Wikidata
Chemical and physical data
FormulaC17H14O4S
Molar mass314.36 g·mol−1
3D model (JSmol)
  • O=C2OCC(=C2\c1ccccc1)\c3ccc(cc3)S(=O)(=O)C
  • InChI=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 checkY
  • Key:RZJQGNCSTQAWON-UHFFFAOYSA-N checkY
  (verify)

Rofecoxib is a 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 prescription in both tablets and as an oral suspension.[1]

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.[2]

In September 2004, Merck voluntarily 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, allegedly resulting in between 88,000 and 140,000 cases of serious heart disease in the US alone.[3] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market.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.[4]

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.[5] 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.[6]

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.[7] 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,[8] and high potency opioids are the current standard of care in treating HA.[9]

Mode of action

[edit]
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.[10]

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.[11]

Pharmacokinetics

[edit]

The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%.[12][13][14] Rofecoxib crossed the placenta and blood–brain barrier,[12][13][15] and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) around 17 hours.[12][14][16] The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib[12][16] which are primarily excreted through urine.

Efficacy

[edit]

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.[1]

Premenstrual acne

[edit]

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.[17]

Fabricated efficacy studies

[edit]

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, 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 had no comment on the disclosure.[18][19]

Side effects

[edit]
See also: Non-steroidal anti-inflammatory drug
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.[20]  Aside from these features, rofecoxib exhibits a similar adverse-effect profile to other NSAIDs.

Heart and blood vessels

[edit]

VIGOR study and publishing controversy

[edit]

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 mg/day) vs. a common dose of naproxen (500 mg/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.[21]

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.[22][citation needed] 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.[23] Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference,[24] and some outside scientists warned Merck that this claim was implausible before VIGOR was published.[25] 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.[26][27]

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)."[28] 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.[29] 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.[30]

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.[31]

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.[32]

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).[31]

Some scientists have accused the NEJM editorial board of making unfounded accusations.[33][34] Others have applauded the editorial. Renowned research cardiologist Eric Topol,[35] a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trial is really fully backed up".[36] 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".[37]

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."[38]

"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."[38] 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.[39][40][41]

The FDA reviewers were aware of the potential for cardiovascular risk in 1999[42]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.[43]

Alzheimer's disease

[edit]

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

APPROVe study

[edit]

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.[citation needed]

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.[45]

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

[edit]

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.[46][47] 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.[48]

Other COX-2 inhibitors

[edit]

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.[49]

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:[50]

  • 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

[edit]

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 mg/day, diclofenac 150 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).[51][52]

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.[53]

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.[54]

Withdrawal

[edit]

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.[55][56]

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.[57]

On November 5, 2004, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib[58] (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.[59][60] 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.[61]

Martin Report

[edit]

In 2005, Merck spent $21 million to retain John S. Martin Jr., a former District Judge for the Southern District of New York, and his firm, Debevoise & Plimpton, to investigate the Vioxx study results and Merck communications.[62] 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.[63] Merck was satisfied with the report findings and promised to consider its recommendations, while the press criticized its conclusions as self-serving.[62]

FDA position

[edit]

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.[64][65]

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.[66] 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.[6]

Litigation

[edit]

By March 2006, there were over 10,000 cases and 190 class actions filed against Merck[67] 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 Alabama in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use.[68]

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.[69] Merck appealed and the verdict was overturned in 2008.[70] 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 use. The jury ruled that Merck had adequately warned doctors and patients of the drug's risk.[71]

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.[72]

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.[73]

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.[74]

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".[75][76] After the settlement, the lawyers for the case disputed the $315 million awarded in legal fees.[77][78] Ultimately, the judge determined how the fees would be awarded to the plaintiff's attorneys.[79] 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.[80]

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[81] and 10 Years of Tort Reform in Texas Bring Fewer Suits, Lower Payouts.[82]

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.[83] 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.[84]

Possible return to market

[edit]

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.[7] 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,[8] and high potency opioids are the current standard of care in treating HA.[9]

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.[85][86]

On February 15, 2022, California-based BriOri Biotech announced that it had been issued a patent covering topical formulations of rofecoxib.[87]

See also

[edit]

Footnotes

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Rofecoxib

View on Grokipedia
from Grokipedia

Rofecoxib is a selective (COX-2) inhibitor classified as a (NSAID), developed and marketed by under the brand name Vioxx for relieving signs and symptoms of , , acute pain in adults, and primary . Approved by the U.S. (FDA) on May 20, 1999, following clinical trials demonstrating efficacy comparable to traditional NSAIDs with reduced gastrointestinal toxicity due to its COX-2 selectivity, rofecoxib achieved peak annual sales exceeding $2.5 billion and was prescribed to over 80 million patients worldwide. However, Merck voluntarily withdrew it from the market on September 30, 2004, after the APPROVe trial revealed a doubled of serious cardiovascular events, including and , after 18 months of use compared to , prompting regulatory actions and extensive litigation. The drug's development stemmed from efforts to mitigate the ulcerogenic effects of non-selective NSAIDs by targeting COX-2, an induced during inflammation, while sparing COX-1, which maintains gastric mucosal integrity; pre-approval studies like VIGOR suggested cardiovascular signals that were controversially attributed to cardioprotective effects of comparator naproxen rather than inherent risks of rofecoxib. Post-withdrawal analyses confirmed elevated thrombotic risks with long-term exposure, influencing subsequent scrutiny of COX-2 inhibitors and broader NSAID safety profiles, though debates persist on absolute risk magnitudes and comparative benefits against gastrointestinal harms. Merck faced thousands of lawsuits alleging concealment of data, resulting in settlements totaling billions, yet from trial endpoints underscored the causal link between prolonged COX-2 inhibition and prothrombotic states via mechanisms like reduced synthesis without platelet COX-1 inhibition.

Development and Regulatory History

Preclinical Development and Discovery

Rofecoxib, chemically designated as 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone and internally coded as MK-0966 by Merck, emerged from efforts at Merck Research Laboratories aimed at identifying selective inhibitors of the inducible (COX-2) enzyme isoform. Following the and of the COX-2 gene in 1991, which revealed its role in without constitutive expression like COX-1, pharmaceutical researchers targeted compounds sparing COX-1 to mitigate gastrointestinal associated with non-selective non-steroidal drugs (NSAIDs). Merck's program optimized furanone derivatives, leading to rofecoxib's synthesis, with its discovery detailed in a 1999 publication describing structure-activity relationships that conferred high COX-2 potency and selectivity. Preclinical biochemical assays demonstrated rofecoxib's selectivity: it inhibited purified COX-2 with an IC50 of 0.11 ± 0.01 μM, while exhibiting no measurable inhibition of COX-1 at concentrations up to 100 μM, yielding a selectivity ratio exceeding 900-fold. In assays, rofecoxib selectively suppressed lipopolysaccharide-induced E2 (PGE2) production (COX-2 marker) with an IC50 of 0.13 ± 0.02 μM, without affecting collagen-stimulated B2 (COX-1 marker) up to 50 μM. These profiles distinguished rofecoxib from non-selective NSAIDs like indomethacin, which inhibit both isoforms comparably. In vivo pharmacological evaluations in rodents confirmed efficacy and safety advantages. Oral rofecoxib reduced carrageenan-induced paw with an ED50 of 1.3 mg/kg, equipotent to indomethacin, and alleviated yeast-induced in . Critically, at doses, rofecoxib caused minimal gastric lesions—less than 1 per in models—contrasting sharply with indomethacin's induction of 20-30 lesions, underscoring its COX-1-sparing potential for gastrointestinal tolerability. Pharmacokinetic studies revealed good oral , with plasma supporting once-daily dosing in humans. These preclinical findings, including potency in air-pouch models and lack of COX-1-dependent platelet aggregation inhibition, positioned rofecoxib as a promising candidate for advancing to clinical trials by 1995, amid the first wave of COX-2 selective inhibitors entering human testing. No cardiovascular signals were evident in these early , which focused primarily on , analgesia, and gastrointestinal endpoints.

Clinical Trials for Approval

The pivotal clinical trials supporting the initial FDA approval of rofecoxib in May 1999 for the relief of of , management of acute , and treatment of primary consisted of multiple phase III studies involving approximately 5,400 s across eight trials. For , four key studies demonstrated efficacy, including two 6-week placebo-controlled trials with active comparators such as , where rofecoxib at 12.5 mg and 25 mg daily doses showed statistically significant improvements in and physical function measures (e.g., WOMAC scores) compared to , with efficacy comparable to the active comparators. These trials enrolled patients with moderate-to-severe of the or , using primary endpoints like patient global assessment of response to and medication use, with rofecoxib reducing symptoms by 40-50% in responders. In acute pain models, particularly post-dental surgery extraction studies (e.g., protocol 071), rofecoxib at 50 mg provided significant analgesia, outperforming placebo in stop-watch assessments of pain relief over 24 hours and reducing the need for rescue analgesics, with onset comparable to ibuprofen 400 mg but sustained duration exceeding 12 hours. Similar efficacy was observed in primary dysmenorrhea trials, where single-dose rofecoxib 50 mg alleviated pain intensity and associated symptoms more effectively than placebo, with effects lasting up to 24 hours. Safety data from these short-term (typically 6 weeks or less for chronic use, single-dose for acute) placebo- and active-controlled trials indicated a lower incidence of gastrointestinal adverse events, such as ulcers and bleeding, compared to non-selective NSAIDs, with no clinically significant increase in cardiovascular thrombotic events detected, though event rates were low overall due to limited exposure duration and patient numbers. Approval for indications followed in 2002 via supplemental NDA, supported by additional data from trials like protocol 096, a 12-week study comparing rofecoxib 25 mg to and naproxen, showing superior improvements in ACR20 response criteria (percentage of patients achieving at least 20% reduction in tender/swollen joint counts and other measures) versus . These trials prioritized demonstration of non-inferiority to standard NSAIDs in while highlighting COX-2 selectivity benefits for tolerability, but their relatively brief durations (up to 12 weeks) and focus on GI endpoints masked potential long-term cardiovascular risks that emerged in subsequent post-marketing studies.

FDA Approval and Initial Indications (1999)

The U.S. Food and Drug Administration (FDA) granted approval for rofecoxib, developed and marketed by Merck & Co. under the brand name Vioxx, on May 20, 1999, via New Drug Applications (NDAs) 021042 and 021052. The approval authorized oral tablets in 12.5 mg and 25 mg strengths, positioning rofecoxib as a selective cyclooxygenase-2 (COX-2) inhibitor intended to offer anti-inflammatory and analgesic effects with a lower risk of gastrointestinal adverse events compared to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Initial indications encompassed the relief of signs and symptoms associated with in adults, at recommended doses of 12.5 mg or 25 mg once daily; management of acute pain in adults, at 50 mg once daily not exceeding five days; and treatment of primary , also at 50 mg once daily. These approvals stemmed from pivotal phase III trials, such as the 086 and 090 studies, which enrolled over 1,000 patients with and demonstrated statistically significant improvements in pain and function metrics versus , with efficacy profiles akin to 50 mg three times daily. The FDA's review, completed under the Division of , , and Ophthalmic Products, emphasized rofecoxib's role in addressing unmet needs for patients intolerant to conventional NSAIDs due to upper gastrointestinal issues. Rofecoxib's launch followed closely after the approval of celecoxib (Celebrex) in December 1998, marking the entry of the first COX-2 selective class into the U.S. market amid growing recognition of NSAID-induced gastropathy risks. The initial labeling included standard NSAID precautions, such as warnings for cardiovascular, renal, and hepatic effects, but highlighted endoscopic data suggesting fewer endoscopically detected ulcers than comparator NSAIDs in short-term studies. Subsequent indications, including in 2002, built upon this foundation but were not part of the 1999 approval.

Post-Approval Surveillance and Label Changes

Following FDA approval of rofecoxib on May 20, 1999, post-approval surveillance included ongoing clinical trials, reporting, and pooled analyses of adverse events. The VIGOR (Vioxx Gastrointestinal Outcomes Research) trial, initiated in October 1999, compared rofecoxib 50 mg daily to naproxen 500 mg twice daily in 8,076 patients with ; results published in November 2000 revealed approximately four times as many confirmed myocardial infarctions (MI) in the rofecoxib group (0.4% vs. 0.1%) and a of 2.38 for serious cardiovascular thrombotic events, though Merck and initial interpretations attributed this disparity partly to naproxen's potential cardioprotective effects rather than inherent rofecoxib risk. In response to VIGOR data, the FDA approved a label revision on April 8, 2002, adding a warning for cardiovascular thrombotic events and acute MI, stating that patients with ischemic heart disease should be treated with caution and that the 50 mg dose was not intended for chronic use. That same year, a large epidemiologic study reported a twofold increase in acute MI associated with high-dose rofecoxib (50 mg daily) compared to non-use or lower doses, prompting further scrutiny in post-marketing reports. Post-marketing through 2002 indicated that rofecoxib's organ toxicities, including cardiovascular events, were comparable to those of other nonsteroidal drugs (NSAIDs), with no clear excess signal at standard doses (12.5–25 mg) in early voluntary reporting systems. Subsequent surveillance encompassed additional trials and meta-analyses. The APPROVe (Adenomatous Polyp Prevention on Vioxx) trial, evaluating rofecoxib 25 mg daily versus for recurrence in 2,586 patients, showed in interim analysis after (conducted in 2004) a doubled of confirmed thrombotic cardiovascular events ( 1.92; 1.50 events per 100 patient-years in rofecoxib group vs. 0.78 in ), with risks emerging as early as of use. Pooled analyses of placebo-controlled trials up to 2009 confirmed a dose-dependent trend toward elevated cardiovascular , with cumulative s increasing over time (e.g., 1.34 for all doses after ). These findings, absent a placebo arm in VIGOR and debated interpretations of naproxen effects, culminated in Merck's voluntary worldwide withdrawal of rofecoxib on September 30, 2004, after FDA consultation, as the risks outweighed benefits for chronic use.

Pharmacological Properties

Mechanism of Action as a COX-2 Selective Inhibitor


Rofecoxib selectively inhibits (COX-2), one of two isoforms of the that catalyzes the conversion of to (PGH2), the precursor for prostanoids involved in , , and fever. COX-2 is inducible by cytokines and growth factors at sites of or , whereas COX-1 is constitutively expressed and maintains physiological functions such as gastric mucosal integrity and platelet aggregation. By targeting COX-2, rofecoxib suppresses the production of pro-inflammatory prostaglandins like PGE2 while sparing COX-1 activity, theoretically reducing gastrointestinal associated with non-selective NSAIDs. The molecular basis for this selectivity lies in structural differences between the COX isoforms: the COX-2 features a larger hydrophobic channel (approximately 20% wider than in COX-1) due to the substitution of smaller , such as Val523 (COX-2) versus bulkier Ile523 (COX-1), creating an accessible side pocket. Rofecoxib's diarylheterocycle scaffold, including its 4-(methylsulfonyl), exploits this side pocket for enhanced binding affinity to COX-2 via hydrogen bonding and hydrophobic interactions, as revealed by crystal structures showing the molecule occupying the upper region of the channel and blocking substrate access. This binding is time-dependent for COX-2, forming a stable enzyme-inhibitor complex with an of 0.34 μM in assays using purified human recombinant COX-2, compared to non-time-dependent and much weaker inhibition of COX-1. In human ex vivo assays, which better reflect physiological conditions, rofecoxib demonstrates potent COX-2 inhibition ( ≈ 0.53 μM) with selectivity ratios (COX-1 / COX-2 ) ranging from 35 to over 100, ensuring negligible COX-1 suppression at therapeutic doses up to 50 mg. These properties confer high specificity, as confirmed by doses exceeding 10-fold therapeutic levels failing to inhibit COX-1-derived in platelets.

Pharmacokinetics and Metabolism

Rofecoxib is rapidly absorbed following , with peak plasma concentrations typically achieved within 2 to 3 hours. Its is approximately 93% at therapeutic doses of 12.5 mg, 25 mg, and 50 mg, and food intake has minimal impact on the rate or extent of absorption. The drug exhibits high , approximately 87%, primarily to , and has a steady-state of about 91 liters, indicating moderate tissue distribution. Rofecoxib undergoes extensive hepatic , with less than 1% of unchanged recovered in . Primary metabolic pathways include oxidation to 5-hydroxyrofecoxib and subsequent , as well as reduction to the cis-dihydrodiol, with no significant involvement of enzymes in the major routes; however, it acts as a metabolism-dependent inhibitor of CYP1A2. Elimination occurs predominantly via hepatic followed by biliary into , where about 14% of a dose appears as unchanged and the remainder as metabolites; urinary accounts for approximately 72% of the dose, primarily as metabolites. The terminal elimination is approximately 17 hours at , supporting once-daily dosing.

Clinical Efficacy

Efficacy in Osteoarthritis and Rheumatoid Arthritis

Rofecoxib, at doses of 12.5 mg or 25 mg once daily, demonstrated significant efficacy in reducing and improving function in patients with (OA) of the , , or other joints, as shown in randomized controlled s comparing it to , acetaminophen, and other nonsteroidal anti-inflammatory drugs (NSAIDs). In a 6-week multicenter involving 512 patients with OA, rofecoxib 25 mg provided superior relief and functional improvement compared to acetaminophen 4,000 mg daily, celecoxib 200 mg daily, and rofecoxib 12.5 mg, with statistically significant differences in patient global assessment of response to (PGART) and WOMAC subscale scores (P < 0.05 for key endpoints). Efficacy was consistent across patient subgroups, including those with or OA, unilateral or bilateral involvement, and varying numbers of affected joints, with no significant differences by age, sex, race, or prior . Additionally, rofecoxib exhibited a faster onset of analgesia, with measurable improvements in scores within the first 6 days of treatment, outperforming comparators like celecoxib and in early response rates. Long-term studies, such as a one-year against 100 mg daily, confirmed sustained efficacy comparable to traditional NSAIDs, with similar reductions in joint and disability. In (), rofecoxib at 25 mg or 50 mg once daily provided effective symptom relief, including reductions in joint pain, tenderness, and swelling, outperforming in short-term trials. A Cochrane review of randomized trials indicated that rofecoxib treatment for 8 weeks resulted in higher rates of symptom relief compared to , with (RR) for global response of 1.75 (95% CI: 1.35-2.26), though evidence quality was moderate due to limited long-term data. In the VIGOR trial, involving over 8,000 , rofecoxib 50 mg daily showed efficacy equivalent to naproxen 1,000 mg daily in controlling disease activity, as measured by American College of Rheumatology (ACR) response criteria, with comparable rates of treatment discontinuation due to lack of efficacy (approximately 14% in both arms). Doses of 25 mg and 50 mg were generally well-tolerated, with maintained over 12 weeks in dose-ranging studies, supporting its approval for management prior to market withdrawal. Overall, rofecoxib's COX-2 selectivity did not compromise its and effects relative to non-selective NSAIDs in these conditions.

Efficacy in Acute Pain, Dysmenorrhea, and Migraine

Rofecoxib demonstrated efficacy in managing acute in several randomized controlled trials, particularly in postoperative settings such as dental surgery. In a single-dose study of adults with following dental impaction removal, rofecoxib at 50 mg provided significant analgesia, with a total pain relief score over 6 hours comparable to ibuprofen 400 mg and superior to , as measured by summed pain intensity differences (SPID). Similar results were observed in orthopedic procedures, including , where preoperative rofecoxib 50 mg reduced postoperative scores and requirements compared to . These effects were attributed to its selective inhibition of COX-2, which mediates inflammatory pathways without initial platelet effects seen in non-selective NSAIDs. For primary , rofecoxib 50 mg once daily was effective in alleviating uterine cramping and associated symptoms in randomized, placebo-controlled trials. A double-blind study of 127 women showed that rofecoxib 50 mg provided greater relief over 12 hours than (mean SPID6 of 8.9 vs. 4.2, P<0.001) and was comparable to naproxen sodium 550 mg, confirming COX-2 involvement in dysmenorrheal . A of individual patient data from multiple trials further supported its efficacy, with for one patient achieving moderate or better relief estimated at 4.1 for 50 mg versus . Daily dosing of 25-50 mg maintained relief with fewer gastrointestinal side effects than traditional NSAIDs in short-term use. In acute treatment, rofecoxib 25 mg and 50 mg doses were superior to in randomized trials, achieving pain-free status at 2 hours in 44-49% of patients versus 24% with . These outcomes were similar to ibuprofen 400 mg, with additional benefits in reducing , , and , and providing sustained 24-hour relief without typical NSAID-related platelet inhibition. A -controlled trial confirmed across migraine severities, though rofecoxib was not ultimately approved for this indication due to later concerns unrelated to acute .

Comparative Efficacy Against Traditional NSAIDs

Rofecoxib demonstrated efficacy comparable to traditional non-selective NSAIDs, such as ibuprofen, naproxen, and , in alleviating pain and improving function in patients with (OA) and (RA). In randomized controlled trials for OA, rofecoxib at 12.5–25 mg daily achieved similar reductions in pain scores and enhancements in physical function, as measured by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) criteria, to ibuprofen at 2400 mg daily or at 100–150 mg daily over 6–12 weeks. These outcomes were consistent across multiple phase III studies, with no significant differences in primary efficacy endpoints between rofecoxib and comparators. In , the VIGOR trial—a double-blind study involving over 8000 patients—found rofecoxib at 50 mg daily to be equivalent to naproxen at 1000 mg daily in reducing signs and symptoms, including joint tenderness and swelling, with both achieving American College of Rheumatology (ACR) response rates exceeding 50% at six months. Pooled analyses of placebo-controlled and active-comparator trials further confirmed rofecoxib's and effects aligned with those of naproxen, ibuprofen, and other traditional NSAIDs, without evidence of superior or inferior performance in symptom control. Network meta-analyses of NSAID efficacy in OA and reinforce this parity, ranking rofecoxib alongside ibuprofen and naproxen in overall treatment scores for pain relief and functional outcomes, though individual responses varied by dose and severity. These findings held across diverse populations, with efficacy maintained in long-term extensions up to 18 months, underscoring rofecoxib's reliability as a therapeutic option prior to safety concerns prompting its withdrawal.

Safety and Risk Profile

Gastrointestinal Benefits and Reduced Ulcer Risk

Rofecoxib exhibited gastrointestinal benefits primarily through its selective inhibition of COX-2, which spares COX-1-derived prostaglandins that maintain gastric mucosal integrity and reduce acid-induced damage, thereby lowering the incidence of and erosions compared to non-selective NSAIDs. In clinical trials, this selectivity translated to significantly fewer upper gastrointestinal adverse events, including perforations, , and bleeds (PUBs). The VIGOR trial, a randomized comparison of rofecoxib (50 mg daily) versus naproxen (1000 mg daily) in 8076 patients over a 9-month follow-up, reported confirmed upper event rates of 2.1 per 100 patient-years with rofecoxib versus 4.5 with naproxen, representing a 50% (P<0.001). Complicated upper events were reduced by 54%, with rates of 0.6 versus 1.4 per 100 patient-years ( 0.46; 95% CI, 0.25-0.85). Additionally, discontinuations due to adverse events were lower with rofecoxib (5.9% versus 8.1%; P=0.005). Endoscopic studies further supported these findings; in a 24-week of patients, rofecoxib (25 or 50 mg daily, supratherapeutic doses) produced gastroduodenal ulcer rates of 5.2% to 11.9%, significantly lower than ibuprofen (2400 mg daily) at 28.5% (P<0.001). Pooled analyses of placebo-controlled trials confirmed a consistently lower incidence of confirmed PUBs with rofecoxib versus comparator NSAIDs over 24.8 months (1.6 versus 4.0 events per 100 patient-years; 0.40; 95% CI, 0.28-0.59). These reductions in ulcer risk and GI events were observed across multiple outcome studies, with COX-2 inhibitors like rofecoxib showing approximately 50% fewer clinical upper GI perforations, , or bleeds compared to traditional NSAIDs, particularly benefiting patients with or those at higher baseline GI risk. However, absolute risk reductions varied by patient factors such as age, prior history, and concomitant infection.

Cardiovascular Risks and Thrombotic Events

Clinical trials of rofecoxib revealed an elevated incidence of cardiovascular thrombotic events, including , , and sudden cardiac death, compared to or active comparators like naproxen. In the VIGOR trial, involving 8,076 patients with randomized to rofecoxib 25 mg daily or naproxen 500 mg twice daily for a of 9 months, the rofecoxib group experienced 45 confirmed myocardial infarctions versus 11 in the naproxen group, yielding a of 4.00 (95% CI 2.01-8.57). The overall rate of serious thrombotic cardiovascular events was 1.8 per 100 patient-years in the rofecoxib arm compared to 0.7 per 100 patient-years with naproxen, with a of 2.38 (95% CI 1.39-4.00). The risk profile appeared dose- and duration-dependent, with early signals in shorter-term studies but clearer elevation in longer exposures. Pooled analyses of placebo-controlled trials, encompassing over 23,000 patients across doses of 12.5 mg and 25 mg daily, indicated a of 1.35 (95% CI 0.99-1.84) for cardiovascular thrombotic events or death through June 2001, representing a 35% increase. Cumulative meta-analyses of randomized trials further demonstrated a of 2.30 (95% CI 1.33-4.00) for acute , with statistically significant evidence emerging from data available by November 2000. The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, a placebo-controlled study of 2,586 patients with prior colorectal adenomas receiving rofecoxib 25 mg daily for up to 3.5 years, reported a of 1.92 (95% CI 1.19-3.04) for the composite endpoint of cardiovascular death, , or after 18 months, prompting early termination on September 27, 2004, due to excess events (46 in rofecoxib versus 20 in ). This translated to primarily increased and ischemic cerebrovascular accidents, with the divergence in Kaplan-Meier event rates becoming apparent beyond 12 months. Follow-up data indicated persistence of elevated risk for at least post-discontinuation in some cohorts. These observations, corroborated across multiple datasets, underpinned Merck's voluntary worldwide withdrawal of rofecoxib on , 2004, as the risks outweighed benefits for its indications. Regulatory assessments by the FDA affirmed the association with heightened thrombotic events during chronic use, particularly at therapeutic doses.

Key Studies on Cardiovascular Outcomes

The VIGOR (Vioxx Gastrointestinal Outcomes Research) trial was a multicenter, randomized, double-blind study published in November 2000 that enrolled 8,076 patients with to compare the upper gastrointestinal toxicity of rofecoxib (50 mg once daily) versus naproxen (500 mg twice daily) over a mean duration of 9 months; low-dose aspirin was prohibited. Although the primary endpoint focused on gastrointestinal events, prespecified secondary analyses revealed a higher rate of confirmed s in the rofecoxib group (17 events, 0.4%) compared to naproxen (4 events, 0.1%), yielding a of 4.00 (95% CI, 1.20 to 17.98). For the broader composite endpoint of serious cardiovascular thrombotic events (, , cardiac , resuscitated , sudden or unexplained death, or ischemic ), the was 2.38 (95% CI, 1.39 to 4.00), with 45 events (0.6%) in the rofecoxib group versus 19 (0.2%) in the naproxen group. The APPROVe (Adenomatous Polyp Prevention on Vioxx) trial, a randomized, -controlled, double-blind study published in September 2005, assessed the efficacy of rofecoxib (25 mg daily) in preventing recurrent colorectal adenomas in 2,586 patients with prior adenomas, with treatment planned for 3 years but terminated early at 33 months. An after a mean follow-up of 25.5 months (with risk assessed after ) identified 46 adjudicated adverse cardiovascular events (confirmed , , , sudden cardiac death, , , or peripheral arterial thrombosis) in the rofecoxib group versus 20 in , corresponding to a of 1.92 (95% CI, 1.19 to 3.11; P=0.008). The absolute risk increase was 0.8 percentage points (1.9% vs 1.1%), and a 2006 correction to the noted that the divergence in Kaplan-Meier curves for cardiovascular risk emerged as early as 5 months, not solely after as initially reported. A of 138 randomized, placebo-controlled trials sponsored by Merck, encompassing data from approximately 49,000 patients exposed to rofecoxib (predominantly at 25 mg daily for ), reported a of 1.39 (95% CI, 1.00 to 1.94) for the composite cardiovascular endpoint (, , or vascular death), with the risk appearing dose-dependent and more pronounced at higher doses or longer durations. Independent cumulative meta-analyses of published and unpublished rofecoxib trials similarly confirmed an elevated risk of , with signals detectable as early as 2000 from VIGOR data integrated with smaller studies.

Other Adverse Effects and Long-Term Safety Data

Rofecoxib was associated with common non-serious adverse effects including , , and , occurring at incidences of approximately 5-10% in clinical trials, comparable to or other NSAIDs. was reported in up to 9.5% of patients, higher than with celecoxib (4.9%) but similar to non-selective NSAIDs like ibuprofen. These effects were generally mild and led to discontinuation in less than 2% of cases. Hypertension emerged as a notable , with rofecoxib at 25 mg daily showing a higher incidence in patients compared to lower doses or , including dose-dependent increases in systolic averaging 3-4 mmHg greater than celecoxib. was observed in about 30% of users versus 16% with celecoxib. Renal effects included sodium retention contributing to and , with a of renal dysfunction around 2.3 in meta-analyses, particularly in high-risk groups such as the elderly or those with volume depletion, though acute renal failure was rare outside predisposing conditions. and reduced were also documented in preclinical models and select human cases. Hepatic adverse effects were infrequent, with serum ALT elevations exceeding three times the upper limit of normal in 1.8% of patients versus 0.3% on , but symptomatic injury with occurred rarely (likelihood score C for ), typically resolving upon discontinuation without progression to failure. reactions, including or severe dermatoses like Stevens-Johnson syndrome, were reported sporadically but not at elevated rates beyond class effects. Long-term safety data from trials exceeding one year, such as the 3-year APPROVe study for polyp prevention, showed no substantial increases in non-cardiovascular, non-gastrointestinal serious adverse events beyond short-term patterns, with overall tolerability consistent up to 18-36 months prior to cardiovascular signals prompting withdrawal. No evidence emerged of elevated malignancy risk or unexpected systemic toxicities in extended follow-up, though renal and hypertensive effects warranted monitoring in chronic use, akin to traditional NSAIDs. Post-marketing confirmed these profiles without novel long-term concerns outside the primary withdrawal indication.

Comparisons to Non-Selective NSAIDs and Other COX-2 Inhibitors

Rofecoxib demonstrated efficacy comparable to non-selective NSAIDs such as naproxen and ibuprofen in treating and symptoms, with similar reductions in and improvements in function observed in randomized controlled trials. In the VIGOR trial, involving over 8,000 patients with followed for a of 9 months, rofecoxib at 50 mg daily provided equivalent clinical efficacy to naproxen 500 mg twice daily. Direct comparisons in acute models also showed rofecoxib achieving relief onset and duration similar to non-selective agents like , though with potentially superior overall effects in some assessments. In terms of gastrointestinal safety, rofecoxib exhibited a significantly lower risk of upper gastrointestinal toxicity compared to non-selective NSAIDs. The VIGOR study reported confirmed gastrointestinal events (perforations, ulcers, or bleeds) in 2.1% of rofecoxib-treated patients versus 4.5% with naproxen, representing a of approximately 50%. Pooled analyses of endoscopic studies further confirmed reduced incidence of ulcers with rofecoxib versus comparators like ibuprofen or naproxen, attributing this to its selective inhibition of COX-2 over COX-1, which spares protective synthesis in the . However, cardiovascular safety profiles diverged markedly; the same VIGOR trial indicated a doubled of and other thrombotic events with rofecoxib compared to naproxen (0.4% versus 0.2% incidence), later linked to unopposed thromboxane-mediated platelet aggregation in the absence of naproxen's COX-1 inhibitory cardioprotective effects. Meta-analyses corroborated elevated cardiovascular risks for COX-2 inhibitors like rofecoxib relative to non-selective NSAIDs, with hazard ratios for serious coronary events ranging from 1.4 to 2.3. Comparisons to other COX-2 inhibitors, such as celecoxib and , revealed similarities in gastrointestinal benefits but differences in cardiovascular risk signals and dosing requirements. Rofecoxib and celecoxib both reduced upper gastrointestinal events by 50-60% relative to non-selective NSAIDs in outcomes trials like CLASS (for celecoxib), mirroring VIGOR's findings, though neither eliminated risk entirely in high-risk patients. Direct head-to-head studies indicated rofecoxib often provided superior analgesia to celecoxib; for instance, rofecoxib 50 mg outperformed celecoxib 200-400 mg in postoperative pain relief metrics, potentially due to its longer and potency. Cardiovascular outcomes differed, with case-control data showing rofecoxib associated with higher odds of than celecoxib ( 1.63). Long-term trials suggested comparable dose-dependent risks across COX-2 inhibitors, but rofecoxib's higher selectivity and use at supratherapeutic doses in studies like APPROVe amplified thrombotic hazards, contributing to its earlier withdrawal in , while celecoxib persisted at lower doses with black-box warnings. , structurally similar but withdrawn in 2005 for skin reactions and cardiovascular concerns, shared rofecoxib's elevated relative risks versus non-selective agents in class-wide FDA assessments. Overall, while rofecoxib's profile offered gastrointestinal advantages over non-selective NSAIDs, its cardiovascular liabilities exceeded those of naproxen and paralleled or exceeded other COX-2 inhibitors, underscoring dose and selectivity as key modifiers in risk-benefit evaluations.

Controversies and Scientific Debates

Interpretation of VIGOR Study Data

The VIGOR trial, involving 8,076 patients with rheumatoid arthritis randomized to rofecoxib (50 mg daily) or naproxen (500 mg twice daily) for a median of 9 months, primarily aimed to assess upper gastrointestinal outcomes but also reported on cardiovascular events as a secondary measure. Confirmed adjudicated thrombotic cardiovascular events—defined as myocardial infarction, unstable angina, ischemic stroke, and sudden cardiac death—occurred in 45 patients (0.6%) in the rofecoxib group versus 19 (0.2%) in the naproxen group, with a relative risk of 2.38 (95% confidence interval [CI] 1.25–4.54; p=0.008). Myocardial infarctions specifically affected 37 patients (0.5%) on rofecoxib compared to 7 (0.1%) on naproxen (relative risk 4.25; 95% CI 1.50–17.83). Absolute event rates remained low overall, with total cardiovascular mortality similar between groups (0.2% versus 0.2%). The study's authors, including Merck employees and independent investigators, interpreted the disparity as evidence of naproxen's cardioprotective effects, potentially through inhibition of platelet aggregation similar to aspirin's, unopposed in the rofecoxib arm where low-dose aspirin was prohibited except in a small subset. They argued that rofecoxib lacked interference with such mechanisms but did not actively promote , framing the results as highlighting naproxen's benefit rather than rofecoxib's harm, with no signal in the aspirin-permitted . This view aligned with contemporaneous observational data suggesting modest cardioprotection from naproxen ( 0.86; 95% CI 0.75–0.99 against baselines), though such effects were deemed insufficient to fully account for VIGOR's magnitude in some meta-analyses.17514-4/fulltext) Merck emphasized the trial's GI success—54% relative reduction in events—as supporting rofecoxib's net benefit for at-risk patients, downplaying cardiovascular implications given the rarity of events. Critics, including FDA reviewers and subsequent commentators, contended that the findings indicated an intrinsic prothrombotic risk from selective COX-2 inhibition, which suppresses prostacyclin without curbing thromboxane A2, shifting hemostatic balance toward clotting; naproxen's protection, if any, was viewed as partial and not exonerating rofecoxib, especially as placebo-controlled data later confirmed dose-dependent risks. A 2006 New England Journal of Medicine expression of concern highlighted omissions in the VIGOR publication: three rofecoxib-associated myocardial infarctions, known to authors pre-submission, were excluded, inflating naproxen's apparent benefit and understating rofecoxib's absolute risk (revised MI rate ~0.6% versus 0.1%). This altered subgroup analyses, including those on aspirin use, and raised questions about data transparency, though authors defended the exclusions as unconfirmed at the time and reaffirmed overall conclusions. Retrospective cohort studies found no strong cardioprotective signal for naproxen alone, undermining the primary explanatory hypothesis and reinforcing interpretations favoring rofecoxib's causal role. The debate underscored tensions between relative risks in active comparators versus absolute hazards, influencing early regulatory tolerance despite replicated signals in meta-analyses by 2004.

APPROVe Study Findings and Limitations

The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial was a multicenter, randomized, double-blind, -controlled study enrolling 2,586 patients aged 40 years or older with a history of colorectal adenomas, conducted from February 2000 to early termination in September 2004. Patients received rofecoxib 25 mg daily or matching for up to three years (median follow-up, 33 months), with the primary endpoint of preventing recurrent adenomatous polyps and cardiovascular safety as a prespecified secondary endpoint monitored via an independent data safety committee. Rofecoxib reduced the risk of recurrent adenomas (33.6% incidence versus 45.2% with ; , 0.74; 95% CI, 0.66 to 0.83; P<0.001), confirming efficacy for chemoprevention. However, the trial was halted early after an revealed a doubled of serious cardiovascular thrombotic events with rofecoxib. Confirmed Anti-Platelet Trialists' Collaboration (APTC) composite events—, , or cardiovascular death without another clear cause—occurred in 46 rofecoxib patients (1.50 per 100 patient-years) versus 26 patients (0.78 per 100 patient-years), yielding a of 1.92 (95% CI, 1.19 to 3.11; P=0.008). The excess was driven primarily by nonfatal (23 versus 8) and ischemic cerebrovascular accidents (12 versus 6), with event rates similar in the first (, 0.93) but diverging thereafter (, 1.80 from month 18 onward). Rofecoxib also increased congestive incidence (, 4.61; 95% CI, 1.50 to 18.83; P=0.002), emerging as early as five months, and raised mean systolic by 3.4 mm Hg (versus a 0.5 mm Hg decrease with ; P<0.001). A subsequent extended follow-up confirmed the thrombotic risk elevation, with data compatible with an onset earlier than initially reported and persistence for up to one year post-discontinuation. Limitations of the APPROVe findings include its placebo-controlled design, which isolated rofecoxib's absolute increase over no therapy but precluded direct comparison to active alternatives like naproxen, potentially relative interpretations given evidence of cardioprotective effects from certain traditional NSAIDs. The study population excluded patients with recent cardiovascular events or high- profiles, limiting generalizability to broader patients who comprised most real-world users, and the relatively low event rate (absolute increase of about 1%) reflected this lower-risk cohort rather than higher-risk groups. As cardiovascular events were a secondary endpoint, the trial was not prospectively powered for this outcome, relying on accrued events for significance, and the composite APTC endpoint aggregated heterogeneous events (few fatal; mostly nonfatal) without uniform for all suspected cases. Initial interpretations emphasizing a delayed onset after 18 months were later corrected, as cumulative supported compatibility with earlier divergence, though the precise prothrombotic mechanism—potentially involving unopposed or effects—remained inferential from class-wide COX-2 inhibition rather than trial-specific causation.

Allegations of Data Manipulation and Suppression

Allegations that Merck suppressed or manipulated data on rofecoxib's cardiovascular risks emerged primarily from litigation discovery, internal documents, and testimony by FDA epidemiologist David Graham. In pre-approval studies, such as Merck's Study 090 conducted in the mid-1990s, low-dose rofecoxib was associated with a nearly seven-fold increase in confirmed cardiovascular events compared to , data that Graham alleged was withheld from regulators during the 1999 FDA approval process. Internal Merck discussions from 1996–1997 reportedly explored strategies to exclude high-risk patients from trials to obscure these risks. The VIGOR trial, published in 2000, revealed a five-fold increase in myocardial infarctions for high-dose rofecoxib versus naproxen, which Merck attributed to naproxen's cardioprotective effects rather than rofecoxib's prothrombotic potential; critics, including Graham, claimed Merck minimized the findings by labeling them "preliminary" without disclosure and delayed FDA-mandated labeling updates until April 2002 despite reporting the data in June 2000. Litigation-released emails indicated Merck scientists were aware of cardiovascular signals before VIGOR's publication but prioritized marketing narratives emphasizing gastrointestinal benefits. Ghostwriting practices further fueled claims of manipulation, with Merck drafting at least dozens of rofecoxib-related articles and enlisting academic physicians as nominal authors to lend , as revealed in 2008 analyses of 20 publications where Merck employees were initial leads on 16. In the ADVANTAGE (launched post-approval), Merck allegedly used non-placebo comparators and selective analyses to downplay a four-fold heart attack risk imbalance versus naproxen, removing evidence of events from datasets in some drafts. Internal documents also showed efforts to discredit external critics of rofecoxib's in 2000, including attempts to influence journal publications. Graham testified in November 2004 that these practices contributed to an estimated 88,000–139,000 serious cardiovascular events attributable to rofecoxib, with 30–40% fatal, framing the episode as a failure of both Merck's transparency and FDA oversight. Merck consistently denied intentional suppression, asserting risks were disclosed as evidence emerged and attributing discrepancies to evolving science; however, in , the company settled civil claims for $950 million, including admissions of false statements to programs regarding rofecoxib's cardiovascular safety. While some fraud allegations were litigated unsuccessfully, the disclosures underscored systemic concerns about pharmaceutical influence on research dissemination.

Defenses of Rofecoxib's Risk-Benefit Ratio

Proponents of rofecoxib's continued use in select populations have argued that its gastrointestinal () protective effects substantially outweighed the cardiovascular (CV) risks for patients at elevated risk of complications, such as those with a history of ulcers or . In the VIGOR trial, which compared rofecoxib 50 mg daily to naproxen 500 mg twice daily in patients with , the incidence of confirmed clinically important upper events was 2.1 per 100 patient-years with rofecoxib versus 4.5 per 100 patient-years with naproxen, yielding a of 0.46 (95% CI, 0.25 to 0.85). This approximately 54% reduction in serious events was seen without the need for routine prophylaxis, potentially improving adherence and reducing overall treatment complexity in high-risk or patients. The absolute increase in CV thrombotic events associated with rofecoxib has been characterized as modest, particularly when weighed against alternatives like non-selective NSAIDs, which carry comparable or higher CV risks alongside greater GI toxicity. Cardiologist noted that the relative risk elevation for heart attacks was approximately 1.5-fold over 36 months in long-term studies, but emphasized the low absolute risk, stating that "out of everyone who has a heart attack on Vioxx, maybe Vioxx plays a small, contributory role," with groups experiencing nearly as many events. In the VIGOR , the excess CV events translated to roughly 0.4 additional events per 100 patient-years, a figure argued to be offset by the GI savings in number-needed-to-treat analyses for vulnerable patients. Reanalyses post-withdrawal have reinforced favorable risk-benefit scenarios under patient-centered frameworks, especially compared to contemporary therapies. A 2023 review calculated rofecoxib's net trade-off against naproxen as 2.4 fewer major adverse events per 100 patient-years versus 0.97 more major adverse CV events (MACE), suggesting viability for individuals with uncontrolled refractory to lower-risk options, provided CV risk factors are mitigated. The authors cited a Canadian Expert Advisory Committee recommendation supporting potential rofecoxib reintroduction, based on its established efficacy in relief equivalent to non-selective NSAIDs and the low baseline absolute CV risk in non-high-risk cohorts (e.g., annual event rates under 1%). Such defenses highlight that blanket withdrawal overlooked stratified prescribing, where benefits could yield net health gains measured in quality-adjusted life years for the elderly or comorbid.

Role of Naproxen's Cardioprotective Effects in Relative Risk Assessments

In the VIGOR trial, which compared rofecoxib (50 mg daily) to naproxen (500 mg twice daily) in 8,076 patients with , the of was 2.38 (95% CI 1.19-4.76) favoring naproxen, prompting debate over whether this reflected a prothrombotic effect of rofecoxib or a cardioprotective mechanism of naproxen. Proponents of the latter hypothesis argued that naproxen's inhibition of both cyclooxygenase-1 (COX-1) and COX-2 isoforms might preserve platelet-derived suppression while maintaining endothelial production, potentially mimicking low-dose aspirin's antiplatelet effects. Observational data supported a modest cardioprotective association for naproxen, with a combined of acute of 0.86 (95% CI 0.75-0.99) compared to non-use or other nonsteroidal anti-inflammatory drugs (NSAIDs). However, this effect was small and derived from non-randomized studies, limiting . Subsequent analyses questioned the magnitude of naproxen's protection in explaining VIGOR's findings. Meta-analyses of randomized trials found no significant difference in relative cardiovascular risk for COX-2 inhibitors like rofecoxib when stratified by comparator (naproxen versus placebo or other NSAIDs; p=0.41), suggesting the VIGOR disparity did not uniquely stem from naproxen's benefits. Placebo-controlled trials, such as the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, demonstrated a doubled risk of thrombotic events with rofecoxib (relative risk 1.92; 95% CI 1.26-2.91) after 18 months, independent of naproxen, indicating an absolute prothrombotic signal rather than a relative artifact. Large-scale trials like PRECISION further eroded the cardioprotective narrative, showing naproxen at therapeutic doses (up to 1,000 mg daily) yielded cardiovascular event rates comparable to celecoxib (another COX-2 inhibitor) and ibuprofen, with no noninferiority edge for naproxen (hazard ratio 0.93; 95% CI 0.76-1.13 versus celecoxib). Real-world evidence and pharmacoepidemiologic studies have yielded mixed results on naproxen's profile, complicating its role in calibration for rofecoxib. While some case-control analyses reported reduced acute odds with naproxen versus other NSAIDs (adjusted 0.60; 95% CI 0.44-0.82), population-based cohorts found all NSAIDs, including naproxen, associated with elevated short-term risk ( 1.19; 95% CI 1.11-1.27 for current use). Regulatory assessments, such as those from the U.S. , classify naproxen as carrying a cardiovascular hazard similar to other traditional NSAIDs, without endorsement of protective effects sufficient to offset comparator biases in trials like VIGOR. Thus, while naproxen's potential antiplatelet properties influenced early interpretations of rofecoxib's s—potentially inflating perceived hazards by 20-50% in naproxen-controlled designs—placebo-referenced data and inconsistent observational support indicate this factor alone does not negate rofecoxib's independent thrombotic elevation.

Withdrawal and Regulatory Aftermath

Merck's Voluntary Worldwide Withdrawal (2004)

On September 30, 2004, announced the voluntary worldwide withdrawal of rofecoxib (marketed as Vioxx), a COX-2 selective approved for , , acute , and primary . The decision followed an independent data monitoring committee's recommendation to halt the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, a three-year, placebo-controlled study involving over 2,500 patients with a history of colorectal adenomas, after revealed an increased risk of serious cardiovascular thrombotic events—such as and —in the rofecoxib 25 mg daily arm compared to placebo. Specifically, while no significant risk elevation was observed in the first 18 months (hazard ratio approximately 0.92), the relative risk doubled thereafter, with a hazard ratio of 1.92 (95% 1.19–3.10; p=0.008) for confirmed events beyond that period, prompting Merck to deem the risk unacceptable despite the drug's gastrointestinal benefits. Merck initiated immediate global discontinuation of manufacturing, marketing, and sales, coordinating with regulatory authorities including the U.S. , to which it had reported the trial halt on , 2004. The company notified healthcare professionals worldwide via letters and hotlines, advising gradual tapering for patients on long-term therapy to avoid rebound pain or inflammation, and offered return programs for unused product; no alternative therapy was mandated, but physicians were urged to transition to other analgesics. This action affected approximately 80 million patients who had used Vioxx since its 1999 launch, with Merck emphasizing as the primary driver, independent of commercial considerations, amid prior debates over cardiovascular signals from studies like VIGOR. The withdrawal extended to all formulations and indications, including pediatric use for juvenile , and halted all ongoing clinical trials involving rofecoxib, with Merck committing to further data analysis and publication of APPROVe results. Regulatory bodies outside the U.S., such as the , concurred with the safety concerns, facilitating synchronized global market removal without immediate mandates for competing COX-2 inhibitors like celecoxib. Post-announcement, Merck's stock fell about 27% in a single day, reflecting market anticipation of litigation and revenue loss from a drug that generated $2.5 billion in sales.

FDA's Post-Withdrawal Analysis and Positions

The U.S. (FDA) concurred with Merck's voluntary worldwide withdrawal of rofecoxib on September 30, 2004, stating that from the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial demonstrated an approximate 1.9-fold increase in the of serious adverse cardiovascular events, including and , compared to after 18 months of continuous use at 25 mg daily. The agency noted that this risk emerged after approximately 18 months, with no significant difference observed in the first 18 months, and emphasized that the overall benefit-risk profile for rofecoxib had deteriorated based on cumulative from multiple studies. The FDA did not mandate the withdrawal or issue a recall, characterizing it as a manufacturer-initiated action in response to safety findings that rendered continued marketing untenable. In post-withdrawal reviews, the FDA analyzed integrated data from pre- and post-approval trials, confirming a dose-dependent elevation in cardiovascular thrombotic events associated specifically with rofecoxib, distinct from gastrointestinal benefits that had justified its initial approval in 1999. This assessment informed broader regulatory actions for non-steroidal anti-inflammatory drugs (NSAIDs), including the addition of warnings for cardiovascular risks across the class in April 2005, though the FDA maintained that rofecoxib's profile warranted its removal due to the magnitude of excess risk without offsetting advantages over alternatives. During a joint February 2005 advisory committee meeting of the FDA's Arthritis Drugs and Drug Safety and Risk Management Advisory Committees, panelists reviewed rofecoxib's data alongside other COX-2 inhibitors and voted 17-15 against recommending an outright class ban, instead endorsing restricted access with enhanced labeling for cardiovascular hazards, such as in patients with established heart disease. The committees advised that rofecoxib could theoretically return to market under severe limitations—like short-term, low-dose use in patients intolerant to traditional NSAIDs—but the FDA did not actively pursue reapproval, aligning with Merck's decision to forgo further development. This position reflected the agency's view that while gastrointestinal risk reductions remained valid, unmitigated cardiovascular signals from trials like VIGOR and APPROVe precluded routine use. Subsequent FDA public health advisories, including one issued in early 2005, urged limited prescribing of COX-2 inhibitors only for patients unresponsive to other therapies, underscoring rofecoxib's confirmed prothrombotic effects as a key factor in heightened post-marketing vigilance for NSAIDs. By 2016, the FDA reiterated in updated guidance that rofecoxib's chronic use elevates cardiovascular event risks, supporting the permanence of its market absence without endorsing reformulation efforts. In 2022, the agency formally withdrew approval for rofecoxib formulations at Merck's request, closing out regulatory oversight without reversing prior safety conclusions.

International Regulatory Responses

Following Merck's voluntary worldwide withdrawal of rofecoxib on September 30, 2004, prompted by the APPROVe study's demonstration of doubled risk of serious thrombotic events (including and ) after 18 months of use compared to , international regulatory agencies rapidly endorsed the action and implemented measures to halt distribution and usage. In the European Union, the European Medicines Agency (EMA, then EMEA) convened an urgent meeting with Merck on October 4–5, 2004, and issued guidance on October 6 advising prescribers to review all patients on rofecoxib, discontinue treatment where possible, and switch to alternatives, particularly emphasizing risks for those with cardiovascular factors. The EMA did not issue an independent preemptive suspension but facilitated the suspension of marketing authorizations across member states in alignment with the withdrawal, while launching a class-wide review of COX-2 inhibitors (including celecoxib and etoricoxib) for long-term cardiovascular safety, culminating in updated warnings and contraindications by June 2005. Health Canada notified healthcare professionals and the public of the withdrawal on the same day as Merck's announcement, September 30, 2004, confirming the decision based on emerging cardiovascular data and urging immediate cessation of new prescriptions while advising current users to consult physicians for alternatives. The agency aligned with the voluntary action without mandating a separate , though it contributed to subsequent Canadian reviews of non-steroidal drugs. Australia's (TGA) initiated a Class III recall of all rofecoxib products effective October 1, 2004, directing sponsors, wholesalers, and pharmacies to stock and return it, with notices published in newspapers on ; this enforcement ensured swift market clearance amid recognition of potential thrombotic hazards. Regulatory responses in other regions, such as via the (PMDA), mirrored the global withdrawal without documented independent bans, focusing instead on post-market surveillance enhancements for similar analgesics, though specific enforcement details remain aligned with Merck's initiative. Overall, these actions prioritized patient transition to lower-risk options and spurred international harmonization on COX-2 monitoring, with no reapprovals pursued thereafter.

Litigation and Economic Consequences

Major Lawsuits and Claims of Harm

Following the 2004 withdrawal of rofecoxib (marketed as Vioxx), faced a surge in lawsuits alleging that the drug caused serious cardiovascular harms, including myocardial infarctions, , sudden cardiac death, and other thrombotic events. Plaintiffs contended that rofecoxib increased the of these events by suppressing cardioprotective prostaglandins while failing to inhibit thromboxane-mediated platelet aggregation, with harms purportedly concealed or inadequately disclosed by the manufacturer despite emerging data from trials like VIGOR and APPROVe. By mid-2007, over 27,000 claims had been filed on behalf of approximately 47,000 individuals, many asserting personal injuries or wrongful deaths linked to long-term use of the drug for or acute pain. These actions were primarily consolidated under Multidistrict Litigation (MDL) No. 1657 in the U.S. District Court for the Eastern , encompassing federal cases alleging failure to warn, design defects, and misrepresentation of safety data. Early bellwether trials highlighted the scope of claims: in August 2005, a Texas state court jury in Dodd v. Merck awarded $253 million ($24 million compensatory and $229 million punitive) to the family of a 55-year-old man who suffered a fatal heart attack after eight months of rofecoxib use, finding Merck liable for inadequate warnings. Subsequent trials, such as one in 2006 yielding a $47.5 million for an claiming a heart attack from the drug, underscored allegations of foreseeable risks not reflected in labeling or marketing. Plaintiffs often cited internal Merck documents and post-marketing surveillance suggesting awareness of elevated event rates as early as 2000, arguing these were downplayed to prioritize sales of the blockbuster drug, which had generated over $2.5 billion annually at peak. State court proceedings paralleled the federal MDL, with claims focusing on similar causal links between rofecoxib and adverse , including assertions that the drug's selective COX-2 inhibition profile doubled the of confirmed cardiovascular thrombotic compared to nonselective NSAIDs in certain analyses. Merck contested causation in each case, maintaining that absolute risks remained low (e.g., event rates of 0.74–1.44% in trials) and that many incidents would have occurred absent the drug due to underlying comorbidities like or prior heart disease prevalent in the arthritis patient population. Despite defenses emphasizing comparable risks with alternatives like naproxen or ibuprofen, the volume of filings—reaching nearly 30,000 by some counts—pressured resolution, culminating in a 2007 master settlement program resolving 85–94% of U.S. claims for $4.85 billion without admission of wrongdoing. Residual suits, including international claims, continued into the , with some verdicts overturned on appeal citing insufficient proof of specific causation.

Settlements and Financial Impacts on Merck

Following the voluntary worldwide withdrawal of rofecoxib (Vioxx) on September 30, 2004, Merck faced extensive litigation primarily alleging that the drug caused cardiovascular events such as heart attacks and strokes in users. In November 2007, Merck reached a landmark settlement agreement totaling $4.85 billion to resolve approximately 27,000 lawsuits involving over 47,000 plaintiffs who demonstrated qualifying cardiovascular harm attributable to the drug. This fund was structured to compensate verified claims, with Merck contributing payments incrementally, including an initial $500 million tranche in August 2008. The settlement did not admit liability but aimed to avert prolonged trials, following mixed jury verdicts in earlier cases, such as a $253 million award (later reduced) in one trial. Additional settlements addressed regulatory and marketing violations tied to rofecoxib promotion. In May 2008, Merck agreed to pay $58 million to resolve 30 state lawsuits claiming deceptive television advertisements that downplayed cardiovascular risks while emphasizing gastrointestinal benefits. Separately, in November 2011, Merck entered a deferred prosecution agreement with the U.S. Department of Justice, paying $321.636 million in criminal penalties and $628.364 million in civil settlements for off-label promotion of rofecoxib (among other drugs), including inducements to physicians and false statements to federal healthcare programs. These resolved False Claims Act allegations but were part of broader scrutiny, with the civil portion split between federal ($426.389 million) and state recoveries ($201.975 million). The cumulative financial burden exceeded settlements alone, incorporating defense costs and lost revenue. By mid-2008, Merck had incurred at least $6.38 billion in total Vioxx-related expenses, including over $1.53 billion in legal fees, expert research, and administrative outlays through 2008. Rofecoxib generated $2.5 billion in annual prior to withdrawal, representing about 11% of Merck's global pharmaceutical revenue in 2003 and contributing to a projected 20% profit decline in 2004. Fourth-quarter 2004 losses from the drug were estimated at $700–750 million. Despite these impacts, Merck's overall financial position stabilized post-settlement, with no bankruptcy risk materializing, though the episode prompted strategic shifts including R&D reallocations and reliance on other products like statins.

Estimates of Attributable Cardiovascular Events

In pharmacoepidemiological analyses conducted post-withdrawal, estimates of excess cardiovascular events attributable to rofecoxib centered on myocardial infarctions (MI) and sudden cardiac deaths, extrapolated from relative risks observed in clinical trials and observational data applied to U.S. exposure patterns from 1999 to 2004. An internal FDA safety review by epidemiologist David J. Graham in 2004 projected approximately 27,000 to 28,000 excess cases of MI or sudden cardiac death linked to rofecoxib, based on pooled data from Merck-sponsored trials indicating a relative risk of about 2.3 for these events compared to placebo or non-naproxen nonsteroidal anti-inflammatory drugs (NSAIDs). A nested case-control study by Graham et al., analyzing 1.39 million patient records from a health plan, estimated 88,000 to 140,000 excess cases of serious coronary heart disease (acute MI or sudden cardiac death) nationwide over rofecoxib's market life, reflecting a of 3.58 (95% CI 1.00-12.81) versus non-naproxen NSAIDs after adjusting for confounders like age and comorbidities. This projection incorporated underascertainment factors and assumed 27% to 44% of rofecoxib users would have experienced events even with alternative therapies, yielding an attributable fraction of 56% to 73%.17710-8/fulltext) Of these excess cases, 30% to 40%—or roughly 27,000 to 56,000—were deemed fatal, consistent with typical mortality rates for serious coronary events. These figures informed litigation claims, with plaintiffs citing the higher range to argue widespread , while Merck contested the models for over-relying on high-risk subgroups and underestimating NSAID risks. Independent validations, such as cumulative meta-analyses of trial data, corroborated elevated relative risks emerging as early as 2000 but emphasized absolute risks remained low (about 1-2 additional events per 1,000 patient-years) in lower-risk populations.

Broader Implications and Future Prospects

Public Health Trade-Offs: GI Savings vs. CV Risks

The VIGOR trial demonstrated that rofecoxib at 50 mg daily reduced the incidence of confirmed upper gastrointestinal events, including perforations, ulcers, and bleeds, by approximately 54% compared to naproxen 1000 mg daily, with event rates of 0.8% versus 1.7% over 9 months in 8076 rheumatoid arthritis patients. This gastrointestinal benefit translated to an estimated 2.4 fewer major adverse GI events per 100 patient-years relative to naproxen, primarily benefiting patients with prior GI history or risk factors. Pooled analyses of other trials confirmed a consistent relative risk reduction of about 50% for clinically significant upper and lower GI events with rofecoxib versus nonselective NSAIDs. In contrast, the same VIGOR trial revealed a doubled of confirmed cardiovascular thrombotic events (, , or sudden death) with rofecoxib compared to naproxen (0.4% versus 0.2% event rates), though this comparison was complicated by naproxen's known cardioprotective effects via platelet inhibition. The placebo-controlled APPROVe trial further quantified the absolute risk, showing a of 1.92 (95% CI 1.19-3.04) for adjudicated thrombotic events with rofecoxib 25 mg daily versus after 18 months in 2586 patients with colorectal adenomas, with risks emerging early and persisting post-discontinuation for up to one year. Population-level trade-offs hinged on patient stratification: for individuals at high GI risk (e.g., elderly with history) but low baseline CV risk, the GI savings potentially outweighed the CV increment, with modeling suggesting net benefits in targeted subgroups where absolute GI event reductions exceeded CV increases. However, real-world utilization often included patients with unrecognized CV comorbidities—up to 40% in some cohorts—amplifying net harm, as the CV risk elevation (dose- and duration-dependent) offset GI gains across broader populations. Post-withdrawal analyses indicated that while rofecoxib averted thousands of GI hospitalizations during its market presence (1999-2004), attributable CV events numbered in the tens of thousands, prompting regulatory consensus that unrestricted access failed thresholds despite GI advantages. Some panels, including a 2004 Canadian advisory group, argued for conditional reintroduction in low-CV-risk patients, citing unresolved net benefits, but this view was outweighed by evidence of persistent CV hazards.

Lessons for Drug Development and COX-2 Class

The withdrawal of rofecoxib highlighted the necessity for drug development programs to incorporate long-term cardiovascular outcome trials, particularly for agents intended for chronic use in populations with elevated baseline risks, as shorter-term studies like the VIGOR trial (published in 2000) failed to detect signals that emerged after 18 months of exposure in the APPROVe trial, which demonstrated a relative risk of 1.92 for adverse cardiovascular events compared to placebo. This underscored that selective COX-2 inhibition disrupts the balance between prostacyclin (vasodilatory and antithrombotic) and thromboxane A2 (prothrombotic), potentially amplifying thrombotic risks over time, a mechanism confirmed in subsequent meta-analyses showing approximately 40% increased major vascular events with coxibs versus nonselective NSAIDs. Misinterpretation of early data, such as attributing rofecoxib's apparent cardiovascular safety in VIGOR to cardioprotective effects of the naproxen comparator without confirmatory evidence, illustrated pitfalls in comparative and the risks of in sponsor analyses; independent re-evaluations revealed unadjusted ratios indicating harm as early as internal Merck discussions predating approval in 1999. For the COX-2 class, this prompted recognition of a dose- and duration-dependent class effect, with low doses of rofecoxib and celecoxib still elevating risks while offering gastrointestinal benefits, leading developers to prioritize balanced COX inhibition or adjunctive therapies like inhibitors over pure selectivity. Regulatory reforms post-withdrawal emphasized enhanced , including mandatory risk evaluation and mitigation strategies (REMS) and the FDA's Critical Path Initiative to integrate safety signals earlier in development, reducing reliance on post-marketing that delayed rofecoxib's risk identification despite preclinical concerns about . These lessons shifted NSAID development toward proactive cardiovascular endpoint in phase III trials and transparent disclosure prior to licensing, as nondisclosure of dose-related trends in exploratory studies contributed to widespread before full risks materialized. For remaining COX-2 inhibitors like celecoxib, black-box warnings for cardiovascular and gastrointestinal risks were imposed class-wide by , curtailing new entrants without superior safety profiles.

Reformulation Efforts and Potential Reintroduction

Following the 2004 withdrawal of rofecoxib due to increased cardiovascular risks observed in long-term use, Merck & Co. researchers had explored reformulation options as early as 2000 to mitigate those risks, including chemical modifications aimed at preserving anti-inflammatory efficacy while reducing thrombotic potential; however, these efforts did not advance to market prior to withdrawal and were not publicly detailed until internal documents surfaced in litigation. Post-withdrawal, Merck abandoned broad reintroduction plans, citing insufficient evidence of a favorable risk-benefit profile for general arthritis or pain indications, and in September 2022 formally requested the FDA to withdraw approval of the new drug application (NDA 021042), stating a commercial decision against U.S. relaunch. Third-party initiatives have since pursued rofecoxib's revival for niche applications where unmet needs might justify limited risks, often leveraging designations to facilitate development. In 2018, Tremeau Pharmaceuticals received FDA status for rofecoxib in treating hemophilic , a painful condition in hemophilia patients unresponsive to standard analgesics; by 2019, the company advanced plans for low-dose, targeted use in this rare population (affecting fewer than 200,000 U.S. patients), arguing that burdens and limited alternatives—such as opioids or nonselective NSAIDs with gastrointestinal risks—outweigh cardiovascular concerns in short-term or monitored regimens. Clinical experts have noted potential utility but emphasized unresolved debates over dose-dependent CV hazard, with no phase III trials completed as of 2020. Other reformulation attempts include topical formulations to minimize systemic exposure and CV effects. BriOri BioTech announced in 2022 development of a rofecoxib-based ointment for localized pain relief, aiming to bypass oral issues that amplified risks in original trials; this approach draws on precedents like gels but faces hurdles in proving non-inferiority to existing topicals without inheriting vascular liabilities. Exploratory proposals for acute treatment have surfaced, positing short-duration dosing could limit exposure below risk thresholds seen in chronic studies (e.g., APPROVe trial's 18-month ), though neurologists highlight persistent mechanistic concerns tied to COX-2 selectivity and unaddressed endothelial effects. As of 2025, no reformulated rofecoxib product has gained regulatory approval, reflecting regulatory caution, lingering litigation shadows, and demands for prospective CV safety data in targeted cohorts.

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