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 as 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 associated with long-term, high-dosage use. 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withdrawn from the market.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.[1]
Rofecoxib was available on prescription as tablets and as an oral
suspension.
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 peptic ulcers.
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
-
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.[citation needed]
Withdrawal from the market
VIGOR study
The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., which compared the efficacy and adverse effect
profiles of rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the
study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from
cardiovascular events between the two groups, nor was there any significant difference in the rate of myocardial infarction
between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk
was accounted for by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin
prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular
accident, transient ischemic attack, or coronary artery bypass).
Merck's scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart
attacks "is primarily due to" this protective effect (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 trial 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].
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."[2]
"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."[2]
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 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 study of 114 randomized trial comprised of 116,000+ participants, published in JAMA, showed that
Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia. COX-2 Inhibitor Drug Review of adverse renal and arrhythmia risk, in JAMA 2006
Withdrawal
Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market
worldwide on September 30, 2004.
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 30, 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 5, 2006, the jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded Mr McDarby $4.5
million in compensatory damages based on Merck's failure to properly warn of Vioxx safety risks. After a hearing on April 11,
2006, the jury also awarded Mr McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the
heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial.
Merck has reserved $970 million to pay for its Vioxx-related legal expenses through 2007.
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, evaluated 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.[15]
Negative cardiovascular effects in the majority of NSAIDS
Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with the majority of
NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed
trials that could establish such effects and these sort of trials have never been carried out in older "trusted" nsaids such as
ibuprofen, diclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet properties.
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 [16].
- 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. [17]
- 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. [18]
- Wolfe, MM et al, Gastrointestinal Toxicity of Nonsteroidal Anti-anflamattory Drugs, New England Journal of Medicine. 1999;
340; 1888-98.
External links
|
Non-steroidal anti-inflammatory drugs
(primarily M01A and M02A, also N02BA) |
| Salicylates |
Aspirin (Acetylsalicylic
Acid), Diflunisal, Ethenzamide, Salicin |
| Arylalkanoic acids |
Diclofenac, Etodolac, Indometacin,
Nabumetone, Sulindac |
| 2-Arylpropionic acids (profens) |
Carprofen, Flurbiprofen, Ibuprofen, Ketoprofen,
Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Suprofen,
Tiaprofenic acid |
| N-Arylanthranilic acids (fenamic acids) |
Mefenamic
acid |
| Pyrazolidine derivatives |
Phenylbutazone |
| Oxicams |
Meloxicam, Piroxicam |
| Coxibs |
Celecoxib, Etoricoxib, Parecoxib, Rofecoxib,
Valdecoxib, Lumiracoxib |
| Sulphonanilides |
Nimesulide |
| Topically used products |
Diclofenac,
Flurbiprofen, Ibuprofen, Indometacin, Ketoprofen, Naproxen,
Piroxicam, Suprofen |
| Others |
Fluproquazone |
|
Anti-inflammatory and antirheumatic products (M01) |
Anti-inflammatory and
antirheumatic products, non-steroids |
Butylpyrazolidines
(Phenylbutazone, Mofebutazone, Oxyphenbutazone, Clofezone, Kebuzone)
Acetic acid derivatives and related substances (Indometacin, Sulindac, Tolmetin,
Zomepirac, Diclofenac, Alclofenac, Bumadizone, Etodolac,
Lonazolac, Fentiazac, Acemetacin, Difenpiramide, Oxametacin, Proglumetacin, Ketorolac, Aceclofenac, Bufexamac)
Oxicams (Piroxicam, Tenoxicam, Droxicam, Lornoxicam,
Meloxicam)
Propionic acid derivatives (Ibuprofen,
Naproxen, Ketoprofen, Fenoprofen, Fenbufen, Benoxaprofen,
Suprofen, Pirprofen, Flurbiprofen, Indoprofen, Tiaprofenic acid, Oxaprozin, Ibuproxam, Dexibuprofen, Flunoxaprofen, Alminoprofen, Dexketoprofen)
Fenamates (Mefenamic acid,
Tolfenamic acid, Flufenamic acid,
Meclofenamic acid)
Coxibs (Celecoxib, Rofecoxib, Valdecoxib, Parecoxib,
Etoricoxib, Lumiracoxib)
other anti-inflammatory and antirheumatic agents, non-steroids (Nabumetone,
Niflumic acid, Azapropazone, Glucosamine, Benzydamine, Glucosaminoglycan polysulfate, Proquazone, Orgotein, Nimesulide, Feprazone, Diacerein, Morniflumate,
Tenidap, Oxaceprol, Chondroitin sulfate) |
| Specific antirheumatic agents |
Quinolines (Oxycinchophen) - Gold
preparations (Sodium aurothiomalate, Sodium aurothiosulfate, Auranofin, Aurothioglucose, Aurotioprol) - Penicillamine/Bucillamine |
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