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Rofecoxib

Drugs & Medication

Rofecoxib

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Rofecoxib chemical structure
Rofecoxib
Systematic (IUPAC) name
4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one
Identifiers
CAS number 162011-90-7
ATC code M01AH02
PubChem 5090
DrugBank APRD00151
Chemical data
Formula C17H14O4S
Mol. weight 314.357 g/mol
Pharmacokinetic data
Bioavailability 93%
Protein binding 87%
Metabolism hepatic
Half life 17 hours
Excretion biliary/renal
Therapeutic considerations
Pregnancy cat. C (Australia)
Legal status withdrawn
Routes oral

Rofecoxib (IPA: [rofəˈkɒksɪb]) is a nonsteroidal anti-inflammatory drug (NSAID) developed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea. Rofecoxib was approved safe and effective by the Food and Drug Administration (FDA) on May 20, 1999 and was subsequently marketed under the brand name Vioxx, Ceoxx and Ceeoxx.

Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.

On September 30, 2004, Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market.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.(need source)

Rofecoxib was available on prescription as tablets and as an oral suspension.

Contents

Non-Steroidal Anti-Inflammatory Drugs

Rofecoxib belongs to a class of pain relievers called non-steroidal anti-inflammatory drugs or NSAIDS. This class includes many medications sold either over the counter – such as ibuprofen (Advil) and naproxen (Aleve) or by prescription – such as oxaprozin (Daypro) and diclofenac (Voltaren). Like aspirin, which is sometimes classified as an NSAID, traditional NSAIDS work by inhibiting cyclooxygenase (COX), an enzyme that stimulates the synthesis of prostaglandins, chemicals in the body that promote inflammation and pain.

While traditional NSAIDS have long been a mainstay of treatment for patients needing pain relief, this relief does not come without significant adverse side effects—namely a great increase in the risk of gastrointestinal perforations, ulcers, and bleeds or PUBs. Scientists have estimated that NSAID-induced PUBs have caused more than 16,500 deaths and 100,000 hospitalizations annually in the United States. (Wolfe, MM et al, 1999)

The COX Enzyme

In the early 1990s, scientists discovered that the COX enzyme had two forms, now called COX-1 and COX-2. COX-1 mediated the synthesis of prostaglandins responsible for protection of the stomach lining, while COX-2 mediated the synthesis of prostaglandins responsible for pain and inflammation. By creating “selective” NSAIDS that inhibit COX-2, but not COX-1, scientists hypothesized they could offer the same pain relief as traditional NSAIDS, but with greatly reduced risk of fatal or debilitating PUBs.

Rofecoxib is a selective COX-2 inhibitor or coxib (CycloOXygenase-2 InhiBitors). Others include Pfizer’s celecoxib (Celebrex) and valdecoxib (Bextra). Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen. (Bombardier et al., 2000).

Adverse drug reactions

Main article: Non-steroidal anti-inflammatory drug

Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs. Rofecoxib, however, does appear to increase the risk of adverse cardiovascular events (see below).

The chief mechanism proposed to explain rofecoxib's cardiotoxicity is the suppression of prostaglandin, an anti-clotting agent in the blood (Fitzgerald, 2004). COX-2 plays a role in the production of prostaglandin. Because Vioxx inhibits the COX-2 enzyme, prostaglandin production can decrease in endothelial cells and lead to an inefficiency in declumping and vasorelaxtion. Merck, however, argues that there was no effect on prostaglandin production in blood vessels in animal testing.[1] Other researchers have speculated that the cardiotoxicity may be associated with maleic anhydride metabolites formed when rofecoxib becomes ionised under physiological conditions. (Reddy & Corey, 2005)

Vioxx has also been associated with cardiovascular disease, renal (kidney) disease, and heart arrhythmia. COX-2 Inhibitor Drug Review of adverse renal and arrhythmia risk, in JAMA 2006

Withdrawal from the market

VIGOR study

The VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen. (Bombardier et al., 2000), had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups. Nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was accounted for by the patients at higher risk of heart attack: those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, or coronary artery bypass). (Bombardier et al., 2000)

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 (Targum, 2001). Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference (Michaels 2005), and some outside scientists warned Merck that this claim was implausible before VIGOR was published [2]. 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 (Karha and Topol, 2004; Solomon et al., 2002). Though Dr. Topol's 2004 paper criticized Merck's naproxen hypothesis, he himself co-authored a 2001 JAMA article stating "because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a prothrombotic effect from rofecoxib." (Mukherjee, Nissen and Topol, 2001.)

The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001, which led to the introduction, in April 2002, of warnings on Vioxx labelling concerning the increased risk of cardiovascular events (heart attack and stroke).

NEJM controversy

Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, the journal editors learned that certain data reported to the FDA was 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 this data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data (Curfman et al, 2006a). 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.[3]

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." This 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 statitistically insignificant). The editors also noted a statistically significant (2-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication. (Curfman et al., 2006b, Supplementary Material).

The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection and thus were appropriately not included. (Utilizing the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the "omitted" table was printed in the text of the article. The authors stood by the original article. (Bombardier et al., 2006).

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). (Curfman et al., 2006b).

Some scientists have accused the NEJM editorial board of making unfounded accusations.[4], [5] Others have applauded the editorial. Renowned research cardiologist Eric Topol [6], a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trail is really fully backed up" [7]. 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" [8].

Alzheimer's studies

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

APPROVe study

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

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations. (Bresalier et al., 2005)

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

Other studies

Pre-approval Phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first eighteen months of rofecoxib usage (Merck, 2004). Others have pointed out that "study 090," a pre-approval trial, showed a 3-fold increase in cardiovascular events compared to placebo, a 7-fold increase compared to nabumetone (another [NSAID]), and an 8-fold increase in heart attacks and strokes combined compared to both control groups [9] [10]. 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 Merck'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 study of 114 randomized trial comprised of 116,000+ participants, published in JAMA, showed that Vioxx uniqued increased risk of renal (kidney) disease, and heart arrhythmia. COX-2 Inhibitor Drug Review of adverse renal and arrhythmia risk, in JAMA 2006

Withdrawal

Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.

In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.

On November 5 the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (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. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Juni omitted several studies that showed no increased cardiovascular risk. (Merck & Co., 2004).

In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib's benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen[11] -- though the panel recommended that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market.

Litigation

As of March 2006, there had been over 10,000 cases and 190 class actions filed against Merck 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.[12]

On August 19, 2005, a jury in Texas voted 10-2 to hold Merck liable for the death of Robert Ernst, a 59-year old man who allegedly died of a rofecoxib-induced heart attack. The plaintiffs' lead attorney was Mark Lanier. Merck argued that the death was due to cardiac arrhythmia, which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award will almost certainly be capped at no more than USD$26.1 million because of punitive damages limits under Texas law.[13] As of March 2006, the plaintiff had yet to ask the court to enter a judgment on the verdict; Merck has stated that it will appeal.

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.[14]

The first federal trial on rofecoxib, Plunkett v. Merck, began on November 29, 2005 in Houston, Texas. The trial ended in a hung jury and a mistrial was declared on December 12, 2005. According to the Wall Street Journal, the jury hung by an eight to one majority, favoring the defense. Upon retrial in February 2006 in New Orleans, Louisiana, where the Vioxx multi-district 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.

On January 30th, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastiointestinal 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 punitive amount will be reduced to under $1 Million.

On April 5th, the judge overseeing the MDL litigation dismissed Diaz v. Merck on request of the plaintiff. Merck attorney Phil Beck said that the decision of the Plaintiff Steering Council – a group of lawyers coordinating federal cases against Merck -- to not support “Mr. Diaz' case reflects the evidence proving that Mr. Diaz's heart attack was not caused in any way by his use of Vioxx for 19 months.” Diaz’s attorney said the request was made because there were too many documents to go through, although the trial date had already been delayed twice. [15]

Merck successfully defended in Doherty v Merck where a grandmother claimed that the drug had caused her heart attack. The jury in Atlantic City, New Jersey found that Vioxx did not contribute to her heart attack, that Merck acted responsibly in informing the medical community about the benefits and risks of the drug and that the drug company's marketing efforts did not mislead consumers. [16]

In August 2006, a jury found in favor of Merck in the company's first case in California, Grossberg v. Merck. The jury found that Merck was not negligent, that it did not conceal information and that Vioxx did not cause Grossberg’s heart attack. [17]

Merck has reserved $970 million to pay for its Vioxx-related legal expenses through 2007.

Merck sales representatives are now being subpoenaed to court over selling Vioxx to doctors- patients are claiming the reps knew of the side effects and are partially responsible for the wrongful deaths.

Political impact of Vioxx litigation in America

The recall and litigation over rofecoxib has provoked debate over drug safety in the United States. Some argue that the U.S. Food and Drug Administration does not do enough to monitor product safety and that the rofecoxib withdrawal is an argument against tort reform. It has also been argued that litigation is an imperfect means of regulation that would overdeter companies for complying with FDA requirements, and that large awards like that in Ernst would inhibit research and development.

Other COX-2 inhibitors

It is currently unknown whether the increased risk of adverse cardiovascular events is common to all COX-2 inhibitors. Recent studies have demonstrated the increased risk of cardiovascular events associated with the use of celecoxib (Celebrex), valdecoxib (Bextra) and parecoxib (Dynastat). (Solomon et al., 2005; Nussmeier et al., 2005)

Newer and more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), are currently (circa 2005) undergoing Phase III/IV clinical trials. It is likely that these trials will be extended in order to supply additional evidence of cardiovascular safety.

A recent systematic review of 114 clinical trials, published in JAMA 2006, evalated the adverse renal (kidney) and arrhythmia risks of celecoxib, valdecoxib, parecoxib, lumiracoxib, and etoricoxib. COX-2 Inhibitor Drug Review of adverse renal and arrhythmia risk, in JAMA 2006

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 (EMEA 2005):

  • 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

Miscellaneous

  • Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.[18]

References

  • Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al.. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343(21): 1520-8. PMID 11087881
  • Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352(11): 1092-102. PMID 15713943
  • Curfman GD, Morrissey S, and Drazen JM. Expression of Concern Reaffirmed. N Engl J Med 2006; published online February 22. PMID 16495386
  • EMEA (2005) European Medicines Agency, "European Medicines Agency concludes action on COX-2 inhibitors," press release, June 27, 2005. Link
  • FDA (2005). "Summary minutes for the February 16, 17 and 18, 2005, Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee." Published on the internet, March 2005. Link
  • Fitzgerald GA, Coxibs and Cardiovascular Disease, N Engl J Med 2004;351(17): 1709-1711. PMID 15470192.
  • Grassley CE (15 Oct 2004). Grassley questions Merck about communication with the FDA on Vioxx. Press Release.
  • Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M (2004). Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet (published online)
  • Karha J and Topol EJ. The sad story of Vioxx, and what we should learn from it Cleve Clin J Med 2004; 71(12):933-939. PMID 15641522
  • M. A. Konstam et al., “Cardiovascular Thrombotic Events in Controlled, Clinical Trials of Rofecoxib,” Circulation 104 (2001): 2280–2288
  • Michaels, D. (June 2005) DOUBT Is Their Product, Scientific American, 292 (6).
  • Merck & Co., (5 Nov 2004). Response to Article by Juni et al. Published in The Lancet on Nov. 5. Press Release.
  • Merck & Co (30 Sep 2004) Merck Announces Voluntary Worldwide Withdrawal of VIOXX. Press release [19].
  • D. M. Mukherjee, S. E. Nissen, and E. J. Topol, “Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors,” Journal of the American Medical Association 186 (2001): 954–959.
  • Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352(11):1081-91. PMID 15713945
  • Okie, S (2005) "Raising the safety bar--the FDA's coxib meeting." N Engl J Med. 2005 Mar 31;352(13):1283-5. PMID 15800221.
  • Leleti Rajender Reddy, Corey EJ. Facile air oxidation of the conjugate base of rofecoxib (Vioxx™), a possible contributor to chronic human toxicity Tetrahedron Lett 2005, 46: 927. [20]
  • Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002;162:1099-104
  • Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352(11):1071-80. PMID 15713944
  • Swan SK et al., Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet. Annals of Int Med 2000; 133:1–9
  • Targum, SL. (1 Feb. 2001) Review of cardiovascular safety database. FDA memorandum. [21]
  • Wolfe, MM et al, Gastrointestinal Toxicity of Nonsteroidal Anti-anflamattory Drugs, New England Journal of Medicine. 1999; 340; 1888-98.

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