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.
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.
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 Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market.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.
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.
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.
Mode of action
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.
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.
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.
Efficacy Rofecoxib was approved by the FDA to treat osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, acute pain conditions, migraine, and dysmenorrhea. When it was marketed, it gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain.
Premenstrual acne A 2003 placebo-controlled, small, short-term study in India of 80 women with premenstrual acne vulgaris, who were given rofecoxib or placebo for two cycles of 10 days, suggests that "rofecoxib is effective in the management of premenstrual acne.
Fabricated efficacy studies On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as celecoxib) had been fabricated, 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.
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.
Heart and blood vessels VIGOR study and publishing controversy The Vioxx Gastrointestinal Outcomes Research (VIGOR) study led by Claire Bombardier compared the efficacy and adverse-effect profiles of a therapeutic dose of rofecoxib (50 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.
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.
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).
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.
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.
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.
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).
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".