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Gastrointestinal ADRs
In theory the COX-2 selectivity should result in a significantly lower incidence of gastrointestinal ulceration than traditional NSAIDs. The main body of evidence touted to support this theory were the preliminary (6 month) results of the Celecoxib Long-term Arthritis Safety Study (CLASS) as published in 2000, which demonstrated a significant reduction in the combination of symptomatic ulcers plus ulcer complications in those taking celecoxib versus ibuprofen or diclofenac, provided they were not on aspirin (Silverstein et al, 2000). However, this was not significant at 12 months (full study length). It should be noted that this study used a very high dose of Celebrex, 800mg daily (400mg twice a day).
Allergy
Celecoxib contains a sulfonamide moiety and may cause allergic reactions in those allergic to other sulfonamide-containing drugs. This is in addition to the contraindication in patients with severe allergies to other NSAIDs.
Risk of heart attack and stroke
There has been much concern about the possibility of increased risk for heart attack and stroke in users of NSAID drugs, particularly COX-2 selective NSAIDs such as celecoxib, since the withdrawal of the COX-2 inhibitor rofecoxib (Vioxx) in 2004. Like all NSAIDs on the U.S. market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association warned that celecoxib should be used "as a last resort on patients who have heart disease or a risk of developing it", and suggested that acetaminophen, or certain older NSAIDs, such as naproxen, may be safer choices for pain relief in these patients.
The cardiovascular risks of celecoxib are controversial, with apparently contradictory data produced from different clinical trials. In December of 2004, "APC," the first of two trials of celecoxib for colon cancer prevention, found that long-term (33 months) use of high-dose Celebrex (400 and 800mg daily) demonstrated an increased cardiovascular risk compared with placebo. A similar trial, named PreSAP, did not demonstrate an increased risk. Still, the APC trial, combined with the recent Vioxx findings, suggested that there might be serious cardiovascular risks specific to the COX-2 inhibitors. On the other hand, a large Alzheimers prevention trial, called ADAPT, was terminated early after preliminary data suggested that the nonselective NSAID naproxen, but not celecoxib, was associated with increased cardiovascular risk. In April 2005, after an extensive review of data, the FDA concluded that it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs."
Two studies on the cardiovascular risks of celecoxib and other NSAIDs were meta-analyses, published in 2006. The first of these, published in the British Medical Journal, looked at the incidence of cardiovascular events in all previous randomized controlled trials of COX-2 inhibitors, as well as some trials of other NSAIDs. The authors concluded that a significant increased risk did exist for celecoxib, as well as some other selective and nonselective NSAIDS. However, the increased cardiovascular risk in celecoxib was only noted at daily doses of 400 mg or greater. A second meta-analysis published in the Journal of the American Medical Association, which included observational rather than randomized studies (mostly at lower doses) did not find an increased cardiovascular risk of celecoxib vs placebo.
To more conclusively establish the true cardiovascular risk profile of celecoxib, Pfizer has agreed to fund a large, randomized trial specifically designed for that purpose. The trial, centered at the Cleveland Clinic, has a planned enrollment of 20,000 high-risk patients. Celecoxib will be compared to the non-selective NSAIDS naproxen and ibuprofen. Since all patients have arthritis, ethical considerations make it difficult to have a placebo group. This trial has just begun enrollment according to the Clinical Trials database, and is not scheduled to be completed until 2010. Ultimately, this trial will help answer the question as to whether Celebrex has a riskier cardiovascular profile compared to naproxen or ibuprofen.
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