A Comparison of Adverse Renovascular Experiences Among Osteoarthritis Patients Treated with Rofecoxib and Comparator Non-selective Non-steroidal Anti-inflammatory Agents

Summary

Background: Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclo-oxygenase (COX) isoenzymes, i.e. COX-1 and COX-2. Rofecoxib, an agent that selectively inhibits COX-2, has been shown to provide equivalent anti-inflammatory and analgesic efficacy to comparator non-selective NSAIDs in osteoarthritis (OA) and other pain models with a significant improvement in gastrointestinal (GI) safety and tolerability. Based on renal physiology studies, it was predicted that rofecoxib would have renovascular effects similar to those observed with non-selective NSAIDs -specifically edema, blood pressure elevation, attenuation of the effects of ACE inhibitors, and (in rare circumstances), acute renal failure might be manifest in a small percentage of patients.

Objective: To assess the renovascular safety profile of rofecoxib in OA patients compared to that of non-selective NSAID comparators.

Methods: Renovascular adverse experiences (AEs) in over 5000 participants in Phase IIb/III OA clinical trials were reviewed and compared between rofecoxib and non-selective NSAID comparators (ibuprofen 800mg tid, diclofenac 50mg tid, nabumetone 1500mg qd).

Results: The incidence of lower extremity edema (LEE) AEs was generally similar between rofecoxib 12.5mg/day, rofecoxib 25mg/day, and non-selective comparator NSAIDs. Treatment discontinuations due to LEE AEs and clinically significant weight gain (> 2 kg) associated with LEE AEs were infrequent and generally similar in all active treatment groups. Congestive heart failure (CHF) was rare in all treatment groups. The incidence of hypertension AEs was low in all active treatment groups. Discontinuations due to hypertension AEs and hypertension AEs requiring a change or adjustment in blood pressure medications were similar and uncommon in all treatment groups. There was only a single report of acute renal failure (in the ibuprofen treatment group).

Conclusions: In the rofecoxib phase IIb/III OA database, the renal safety profile for rofecoxib, a selective inhibitor of COX-2, was generally similar to that of the comparator, non-selective NSAIDs which were studied.     

The upper gastrointestinal safety of rofecoxib vs. NSAIDs: an updated combined analysis

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific cyclo-oxygenase (COX-1/COX-2) inhibitors and are associated with gastrointestinal (GI) toxicity attributable to COX-1 inhibition. Rofecoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than NSAIDs. OBJECTIVE: To update the results of a previously performed analysis of the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs) with rofecoxib compared with non-selective NSAIDs. Research design and methods: We compared the incidence of PUBs in a combined analysis of 20 randomized, double-blind, clinical trials of rofecoxib versus NSAIDs. Men and women (N = 17,072) from multinational trial sites with osteoarthritis or rheumatoid arthritis were studied. There was no upper age limit in any of the trials. Investigator-reported PUBs were reviewed by a blinded, external adjudication committee using pre-specified criteria. The incidence of confirmed PUBs, the main outcome measure, among patients treated with rofecoxib 12.5 mg, 25 mg, or 50 mg (combined, N = 10 026) was compared to that among patients treated with ibuprofen, diclofenac, nabumetone, or naproxen (combined, N = 7046). RESULTS: The incidence of PUBs over 24.8 months was significantly lower with rofecoxib vs. NSAIDs (cumulative incidence 1.6% vs. 3.1%, p < 0.001; rate/100 patient-years 0.74 vs. 1.87; relative risk 0.36, 95% CI 0.24, 0.54). Results of subgroup analyses and comparisons of rofecoxib with individual NSAID comparators were consistent with the primary result, as was an analysis in patients with no PUB risk factors. DISCUSSION: The analysis demonstrated a consistently lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 24.8 months. These results confirm those of a previous smaller combined analysis of clinical trials with rofecoxib vs. non-selective NSAIDs in OA patients only, in which the risk reduction for confirmed PUBs was approximately 50%. In addition, this analysis demonstrated risk reductions with rofecoxib vs. NSAIDs in risk subgroups and in patients who did not have any known risk factors for PUBs consistent with the primary result. Some of the studies in this analysis required scheduled endoscopies. Asymptomatic upper GI ulcers or bleeding diagnosed during scheduled procedures were not included in the primary endpoint, which may have caused a bias against rofecoxib. CONCLUSIONS: Treatment with rofecoxib was associated with a statistically significantly (p < 0.001) lower incidence of PUBs than was treatment with NSAIDs. The difference was maintained in subgroups of patients with risk factors, as well as in those with no risk factors, for PUBs.     

The upper gastrointestinal safety of rofecoxib vs. NSAIDs: an updated combined analysis*

SUMMARY

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific cyclo-oxygenase (COX-1/COX-2) inhibitors and are associated with gastrointestinal (GI) toxicity attributable to COX-1 inhibition. Rofecoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than NSAIDs.

Objective: To update the results of a previously performed analysis of the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs) with rofecoxib compared with non-selective NSAIDs.

Research design and methods: We compared the incidence of PUBs in a combined analysis of 20 randomized, double-blind, clinical trials of rofecoxib versus NSAIDs. Men and women (N = 17?072) from multinational trial sites with osteoarthritis or rheumatoid arthritis were studied. There was no upper age limit in any of the trials. Investigator-reported PUBs were reviewed by a blinded, external adjudication committee using pre-specified criteria. The incidence of confirmed PUBs, the main outcome measure, among patients treated with rofecoxib 12.5?mg, 25?mg, or 50?mg (combined, N = 10?026) was compared to that among patients treated with ibuprofen, diclofenac, nabumetone, or naproxen (combined, N = 7046).

Results: The incidence of PUBs over 24.8?months was significantly lower with rofecoxib vs. NSAIDs (cumulative incidence 1.6% vs. 3.1%, p < 0.001; rate/100 patient-years 0.74 vs. 1.87; relative risk 0.36, 95% CI 0.24, 0.54). Results of subgroup analyses and comparisons of rofecoxib with individual NSAID comparators were consistent with the primary result, as was an analysis in patients with no PUB risk factors.

Discussion: The analysis demonstrated a consistently lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 24.8?months. These results confirm those of a previous smaller combined analysis of clinical trials with rofecoxib vs. non-selective NSAIDs in OA patients only, in which the risk reduction for confirmed PUBs was approximately 50%. In addition, this analysis demonstrated risk reductions with rofecoxib vs. NSAIDs in risk subgroups and in patients who did not have any known risk factors for PUBs consistent with the primary result. Some of the studies in this analysis required scheduled endoscopies. Asymptomatic upper GI ulcers or bleeding diagnosed during scheduled procedures were not included in the primary endpoint, which may have caused a bias against rofecoxib.

Conclusions: Treatment with rofecoxib was associated with a statistically significantly (p < 0.001) lower incidence of PUBs than was treatment with NSAIDs. The difference was maintained in subgroups of patients with risk factors, as well as in those with no risk factors, for PUBs.     

Benefit-risk assessment of rofecoxib in the treatment of osteoarthritis.

NSAIDs are widely used to treat pain and inflammation in osteoarthritis. Their use in this indication is generally intermittent and fluctuates with the intensity of the disease. Nonetheless, success of the therapy is frequently limited by injury to the gastrointestinal mucosa and complications such as bleeding, ulceration and perforation. A careful and detailed evaluation of these aspects in regard to the newly introduced NSAIDs is of considerable clinical importance. This review focuses on the NSAID rofecoxib, one of the selective cyclo-oxygenase (COX)-2 inhibitors, which are claimed to be as effective as nonselective NSAIDs with better gastrointestinal tolerability. Indeed, phase II, phase III and epidemiological studies have revealed that the efficacy of rofecoxib is comparable to that of conventional NSAIDs but with lower gastrointestinal toxicity, although this advantage may not be demonstrable in every patient. In patients treated with low-dose aspirin (acetylsalicylic acid) for cardiovascular prophylaxis, celecoxib (another selective COX-2 inhibitor) seems to have no obvious advantages over conventional NSAIDs, and similar conclusions may be applied to rofecoxib. A comparison of NSAID therapy +/- concomitant low-dose aspirin was not a primary outcome in this trial with celecoxib and there is thus a need for further studies which compare the gastrointestinal risk of a selective COX-2 inhibitor plus aspirin versus a conventional NSAID. Recent debate has emerged regarding the cardiovascular safety of rofecoxib. Although there is evidence both for and against higher cardiovascular risk with rofecoxib, a retrospective cohort study recently published suggested that there is no increased risk of acute myocardial infarction in the short-term when compared with non-selective NSAIDs. The renal toxicity of rofecoxib has been thoroughly investigated. Clinical studies revealed renal effects of rofecoxib similar to those of conventional NSAIDs. Since adverse effects increase with the degree of renal impairment, monitoring of renal function should be carried out in patients at risk. Although there are still insufficient data concerning certain important adverse effects of rofecoxib, this drug is becoming an important alternative in the therapy of osteoarthritis, especially in high-risk patients. Clinicians need to weigh up the benefits and risks of rofecoxib on a case-by-base basis.     

Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult?

The prevalence of chronic pain increases with age, exceeding 50% in individuals aged ≥65 years. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay of chronic pain management but carry significant dose-related risks of cardiovascular, renal, haematological and other systemic adverse events (AEs). Older patients have an increased risk of these AEs and are more likely to take multiple medications that can potentially interact with NSAIDs. In particular, older patients are more likely to have cardiovascular disease and a natural age-related decline in renal function, increasing the risks of cardiovascular, haematological and renal AEs. Given these risks, recent guidelines for the management of chronic pain in the elderly recommend using NSAIDs rarely and only in carefully selected patients. NSAIDs currently available in the US fall into three categories: nonselective NSAIDs that act via inhibition of cyclo-oxygenase (COX)-1 and COX-2; celecoxib, a selective inhibitor of COX-2; and topical NSAIDs that inhibit both COX-1 and COX-2 but result in much less systemic NSAID exposure than oral formulations. Topical NSAIDs have demonstrated efficacy similar to oral NSAIDs, with an incidence of AEs similar to placebo; however, these agents are an option only in patients with localized pain in superficial joints. Safe pain management in older patients therefore requires cautious choice of selective and nonselective oral NSAIDs, topical NSAIDs or non-NSAID analgesics. This article discusses the risks and benefits of NSAID therapy, reviews its mechanism of action as the source of adverse effects and provides recommendations for maximizing NSAID safety, particularly in older patients. Articles cited in this review were identified via a search of PubMed (January 2005 to November 2009) and a manual search of reference lists from the articles identified in that search. Priority was given to articles discussing NSAID use in older populations, clinical trials of high quality, reports on NSAID safety and AEs, and treatment guidelines.     

Rofecoxib

Rofecoxib (Vioxx?, Merck & Co., Inc.) is a new orally-effective non-steroidal anti-inflammatory drug (NSAID) approved for treatment of acute pain, fever, primary dysmenorrhea and pain and inflammation in osteoarthritis (OA). It is also being evaluated for treatment of rheumatoid arthritis and adenomatous polyps of the colon. Rofecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), thereby inhibiting prostanoid synthesis in cells that express COX-2, including inflammatory cells. As cells in the gastrointestinal (GI) tract principally express COX-1, a different isoform of cyclooxygenase, it is predicted that rofecoxib will have less GI toxicity than other less selective NSAIDs. In clinical trials, rofecoxib was found to be as effective as other NSAIDs for management of pain and inflammation. In trials that compare rofecoxib with ibuprofen, diclofenac and indomethacin, less GI toxicity has been observed, as assayed by a decrease in lesions visible on endoscopy, by GI blood loss and, in a meta-analysis, by frequency of serious adverse GI events. The presence of COX-2 in cells other than inflammatory cells results in side effects common among NSAIDs, including peripheral oedema and hypertension. These side effects are dose-dependent. Rofecoxib, together with other branded NSAIDs, are relatively expensive, which has led to concern regarding costs versus benefits. There is also concern regarding potential risks associated with the use of rofecoxib by populations that would otherwise not tolerate NSAIDs.     

Rofecoxib

Rofecoxib (Vioxx, Merck & Co., Inc.) is a new orally-effective non-steroidal anti-inflammatory drug (NSAID) approved for treatment of acute pain, fever, primary dysmenorrhea and pain and inflammation in osteoarthritis (OA). It is also being evaluated for treatment of rheumatoid arthritis and adenomatous polyps of the colon. Rofecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), thereby inhibiting prostanoid synthesis in cells that express COX-2, including inflammatory cells. As cells in the gastrointestinal (GI) tract principally express COX-1, a different isoform of cyclooxygenase, it is predicted that rofecoxib will have less GI toxicity than other less selective NSAIDs. In clinical trials, rofecoxib was found to be as effective as other NSAIDs for management of pain and inflammation. In trials that compare rofecoxib with ibuprofen, diclofenac and indomethacin, less GI toxicity has been observed, as assayed by a decrease in lesions visible on endoscopy, by GI blood loss and, in a meta-analysis, by frequency of serious adverse GI events. The presence of COX-2 in cells other than inflammatory cells results in side effects common among NSAIDs, including peripheral oedema and hypertension. These side effects are dose-dependent. Rofecoxib, together with other branded NSAIDs, are relatively expensive, which has led to concern regarding costs versus benefits. There is also concern regarding potential risks associated with the use of rofecoxib by populations that would otherwise not tolerate NSAIDs.     

Assessment of the safety of selective cyclo-oxygenase-2 inhibitors: where are we in 2003?

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide despite their well-documented adverse gastrointestinal (GI) effects. The risk of developing a severe GI event varies from patient to patient and NSAID to NSAID. Selective cyclo-oxygenase-2 inhibitors (coxibs) have been designed to have similar efficacy but less GI toxicity than traditional NSAIDs, and have been shown to have an improved GI tolerability and less adverse events across a range of different GI safety assessments. In clinical trials, particularly VIGOR and CLASS, rofecoxib and celecoxib, respectively, significantly reduce the risk of ulcers and ulcer complications than nonselective NSAID comparators with ulcer rates comparable to placebo. The real benefit of a coxib comes from the sparing of the thromboxane and hence preservation of normal platelet function. Thus, there is less risk of bleeding with selective inhibition of COX-2, which is the most common and serious complication of non-selective NSAIDs. Moreover, bleeding can occur anywhere in the GI tract. Although some concern has been raised about the cardiovascular safety of coxibs, when used in recommended doses, there is no convincing evidence that patients treated with a coxib have an increased risk of cardiovascular thrombotic events. Different approaches have been advocated to minimize NSAID-related GI toxicity. Choice of less harmful NSAIDs such as coxib has been one of the strategies promoted in guidelines. The introduction of coxibs with a higher benefit-risk ratio has dramatically changed the therapeutic scenario for anti-inflammatory treatment in the clinical practice.     

Assessment of the safety of selective cyclo-oxygenase-2 inhibitors: where are we in 2003?

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide despite their well-documented adverse gastrointestinal (GI) effects. The risk of developing a severe GI event varies from patient to patient and NSAID to NSAID. Selective cyclo-oxygenase-2 inhibitors (coxibs) have been designed to have similar efficacy but less GI toxicity than traditional NSAIDs, and have been shown to have an improved GI tolerability and less adverse events across a range of different GI safety assessments. In clinical trials, particularly VIGOR and CLASS, rofecoxib and celecoxib, respectively, significantly reduce the risk of ulcers and ulcer complications than nonselective NSAID comparators with ulcer rates comparable to placebo. The real benefit of a coxib comes from the sparing of the thromboxane and hence preservation of normal platelet function. Thus, there is less risk of bleeding with selective inhibition of COX-2, which is the most common and serious complication of non-selective NSAIDs. Moreover, bleeding can occur anywhere in the GI tract. Although some concern has been raised about the cardiovascular safety of coxibs, when used in recommended doses, there is no convincing evidence that patients treated with a coxib have an increased risk of cardiovascular thrombotic events. Different approaches have been advocated to minimize NSAID-related GI toxicity. Choice of less harmful NSAIDs such as coxib has been one of the strategies promoted in guidelines. The introduction of coxibs with a higher benefit-risk ratio has dramatically changed the therapeutic scenario for anti-inflammatory treatment in the clinical practice.     

COX-2 inhibitors and arterial hypertension: an analysis of spontaneous case reports in the Pharmacovigilance database

Objective To evaluate the main characteristics of case reports of arterial hypertension (AH) related to COX-2 inhibitor (coxib) use in real-life practice.Methods This study was based on spontaneous reports of adverse drug reactions (ADRs) submitted to the French Pharmacovigilance system. Associations between AH and the different groups of those using non-steroidal anti-inflammatory drugs (NSAIDs: rofecoxib, celecoxib and non-selective NSAIDs) were compared using calculation of the odds ratio (OR) with 95% confidence intervals (CIs).Results In France, between 1 April 2000 and 30 November 2003, 34 AH cases related to coxibs were reported. Case reports include predominantly patients older than 65 years, with a previous story of essential AH. Most AH (60%) occurred during the first 15 days of treatment. The AH was reported significantly more frequently for rofecoxib than celecoxib. The OR for development of AH with rofecoxib versus celecoxib was 3.3 (1.6–6.9). The AH was also reported more frequently with coxib (2.8%) than with non-selective NSAID (0.5%) use, OR = 5.9 (3.8–9.0).Conclusion This study shows that coxibs are associated with a risk of AH in real-life practice. More spontaneous reports of AH to the French Pharmacovigilance system concern rofecoxib than celecoxib (and coxibs than non-selective NSAIDs). This ADR is of special epidemiological importance due to both the risks of AH and the large use of coxibs.     

Nimesulide is a selective COX-2 inhibitory, atypical non-steroidal anti-inflammatory drug

In this review it is shown that nimesulide, a selective cyclooxigenase-2 (COX-2) inhibitor, is different from other selective COX-2 inhibitors and classical non-steroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory effect mechanism of nimesulide (inhibition of inflammatory mediators) is similar to other classic NSAIDs, but the protective effect of nimesulide on classic NSAID-induced ulcers elucidates the difference between nimesulide and these other drugs. It is known that the selective COX-2 inhibitor nimesulide prevents NSAID-induced ulcers, while celecoxib and rofecoxib, which are more selective to COX-2, failed to prevent these ulcers. Nimesulide produces gastro-protective effects via a completely different mechanism. In addition, while selective COX-2 inhibitors increase the risk for cardiovascular diseases, nimesulide does not exert significant cardiotoxicity. This data suggests that gastrointestinal side effects of classic NSAIDs cannot be related to the COX-1 inhibition alone and also suggest that nimesulide is an atypical NSAID, which is different from both non-selective and selective COX-2 inhibitors.     

Rofecoxib: an update on physicochemical,pharmaceutical, pharmacodynamic and pharmacokinetic aspects

Rofecoxib (MK-966) is a new generation non-steroidal anti-inflammatory agent (NSAID) that exhibits promising anti-inflammatory, analgesic and antipyretic activity. It selectively inhibits cyclooxygenase (COX)-2 isoenzyme in a dose-dependent manner in man. No significant inhibition of COX-1 is observed with rofecoxib up to doses of 1000 mg. The pharmacokinetics of rofecoxib has been found to be complex and variable. Mean oral bioavailability after single dose of rofecoxib (12.5, 25 or 50 mg) is 93% with t(max) varying widely between 2 and 9 h. It is highly plasma-protein bound and is metabolized primarily by cytosolic reductases to inactive metabolites. Rofecoxib is eliminated predominantly by hepatic metabolism with a terminal half-life of approximately 17 h during steady state. Various experimental models and clinical studies have demonstrated rofecoxib to be superior, or at least equivalent, in anti-inflammatory, analgesic and antipyretic efficacy to comparator nonselective NSAIDs in osteoarthritis, rheumatoid arthritis and other pain models. Emerging evidence suggests that rofecoxib may also find potential use as supportive therapy in various pathophysiologic conditions like Alzheimer's disease, and in various malignant tumours and polyps, where COX-2 is overly expressed. Rofecoxib is generally well-tolerated. Analysis of data pooled from several trials suggests that rofecoxib is associated with fewer incidences of clinically symptomatic gastrointestinal ulcers and ulcer complications vis-à-vis conventional NSAIDs. However, this gastropreserving effect may be negated by concurrent use of low-dose aspirin for cardiovascular risk reduction. Rofecoxib tends to show similar tolerability for renal and cardiothrombotic events as compared with nonnaproxen nonselective NSAIDs. No clinically significant drug interaction has been reported for rofecoxib except with diuretics, where it reverses their salt-wasting effect and thus can be clinically exploited in electrolyte-wasting disorders. There is only modest information about the physicochemical and pharmaceutical aspects of rofecoxib. Being poorly water soluble, its drug delivery has been improved using varied formulation approaches. Although it is stable in solid state, rofecoxib is photosensitive and base-sensitive in solution form with its degradation mechanistics elucidated. Analytical determinations of rofecoxib and its metabolites in biological fluids employing HPLC with varied types of detectors have been reported. Isolated studies have also been published on the chromatographic and spectrophotometric assay of rofecoxib and its degradants in bulk samples and pharmaceutical dosage forms. The current article provides an updated overview on the physicochemical, pharmaceutical, pharmacokinetic and pharmacodynamic vistas of rofecoxib.     

Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers

Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.     

Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis

Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for COX-2 than celecoxib, meloxicam, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment.     

Rofecoxib in rheumatoid arthritis: new indication. No better that other NSAIDS

(1) For symptoms of rheumatoid arthritis (pain, joint stiffness), the reference treatment is a nonsteroidal antiinflammatory drug (NSAID) such as diclofenac or ibuprofen. Celecoxib, a coxib NSAID, has no proven advantages over these other NSAIDs. (2) Rofecoxib is the second coxib to be approved in this indication. The clinical evaluation file shows that the optimal daily dose is 25 mg. (3) A comparative trial in more than 8 000 patients, showed that rofecoxib was no more effective than 1 g/day of naproxen. There are no trials comparing rofecoxib with celecoxib, diclofenac or ibuprofen. (4) In clinical trials the overall frequencies of adverse effects and treatment withdrawals for adverse effects were the same for rofecoxib as for other NSAIDs. In one trial, rofecoxib caused fewer gastrointestinal disturbances, particularly serious ones, than naproxen. But rofecoxib caused more gastrointestinal disturbances than placebo. During postmarketing follow up in the United States, a number of deaths due to gastrointestinal complications on rofecoxib were reported. Rofecoxib carries the same renal risk as other NSAIDs. An excess risk of cardiovascular events cannot be ruled out. (5) In practice, the advent of rofecoxib in no way influences the choice of NSAID for symptomatic treatment of rheumatoid arthritis.