Rofecoxib

Overview

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] WP

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] WP

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 United States alone. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market.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.[3][4] WP

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. 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.[5][6] WP

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

Risks and side effects

Side effects

In addition to the reduced incidence of gastric ulceration, rofecoxib exhibits no effect on bleeding time or platelet aggregation, even at supratherapeutic doses. Aside from these features, rofecoxib exhibits a similar adverse-effect profile to other NSAIDs.[1] WP

VIGOR study and publishing controversy

The Vioxx Gastrointestinal Outcomes Research (VIGOR) study led by Claire Bombardier compared the efficacy and adverse-effect profiles of a therapeutic dose of rofecoxib (50 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.[10] WP

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. 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. Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference, and some outside scientists warned Merck that this claim was implausible before VIGOR was published. 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.[11–16] WP⚠ Wikipedia itself has flagged this text: citation needed.

The results of the VIGOR study were submitted to the United States 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)." This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).[17] WP

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. 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.[18][19] WP

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.[20] WP

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.[21] WP

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).[20] WP

Some scientists have accused the NEJM editorial board of making unfounded accusations. Others have applauded the editorial. Renowned research cardiologist Eric Topol, a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trial is really fully backed up". 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".[22–26] WP

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 Medicines own role in aiding Vioxx sales."[27] WP

"Internal emails show the New England Journals 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 NEJMs "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." 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.[27–30] WP

The FDA reviewers were aware of the potential for cardiovascular risk in 1999and 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.[31][32] WP

Alzheimer's disease

In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer's disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk from rofecoxib. Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib's safety.[33] WP

Approve study

In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib, as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib. WP⚠ Wikipedia itself has flagged this text: 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.[34] WP

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. WP

Other studies

Some 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. 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. 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.[34][35][36] WP

Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a retrospective study of 113,000 elderly Canadians published in 2005 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. Another 2005 study comparing celecoxib and refecoxib, using Kaiser Permanente data, found a 1·47 relative risk for low-dose Vioxx usage and 3·58 relative risk for high-dose Vioxx usage, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant.[37][38] WP

Furthermore, a 2006 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.[39] WP

Other COX-2 inhibitors

In 2005, the FDA issued a memo concluding that, along with the other approved COX-2 selective NSAIDs available at the time (i.e., celecoxib, and valdecoxib), rofecoxib was associated with an increased risk of serious adverse cardiovascular events compared to placebo. They also noted that the available data did not permit a rank ordering of these drugs with regard to cardiovascular risk.[5] WP

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

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:[40] WP

• 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[40] WP
• 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[40] WP
• 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[40] WP

Other nsaids

Since the withdrawal of Vioxx, it has come to light that there may be negative cardiovascular effects associated with not only other COX-2 inhibitors, but 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.[41] WP

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 that 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).[42][43] WP

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.[44] WP

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.[45] WP

Withdrawal

As a result of the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.[2][46] WP

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. 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. Furthermore, his analysis only concerned Americans.[47][48][49] WP

On November 5, 2004, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib. 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. 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.[50–53] WP

Martin report

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. 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. Merck was satisfied with the report findings and promised to consider its recommendations, while the press criticized its conclusions as self-serving.[54][55] WP

Pharmacology

Pharmacokinetics

The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%. Rofecoxib crossed the placenta and blood–brain barrier, and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) around 17 hours. The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib which are primarily excreted through urine.[56–60] WP

Chemistry

Formula

C17H14O4S PC

CAS number

162011-90-7 PC

Molar mass (g/mol)

314.4 PC

IUPAC name (computed by PubChem)

3-(4-methylsulfonylphenyl)-4-phenyl-2H-furan-5-one PC

SMILES

CS(=O)(=O)C1=CC=C(C=C1)C2=C(C(=O)OC2)C3=CC=CC=C3 PC

InChIKey

RZJQGNCSTQAWON-UHFFFAOYSA-N PC

PubChem CID

5090

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

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