On 17th December, the U.S. National Cancer Institute (NCI) announced the suspension of the use of Celebrex® in an ongoing clinical trial, the Adenoma Prevention with Celecoxib (APC) because of an increased risk of cardiovascular (CV) events in patients taking Celebrex® versus placebo.

The APC trial compared Celebrex® with placebo for reducing the risk of colon polyps. Approximately 2,000 patients were enrolled, and the average duration of treatment was 33 months. The interim analysis revealed that patients taking 400 mg of Celebrex® twice daily had a 3.4 times greater risk of CV events compared to placebo. For those taking 200 mg of Celebrex® twice daily, the risk was 2.5 times greater.

A separate long-term study sponsored by Pfizer (Prevention of Spontaneous Adenomatous Polyps (PreSAP)) comparing Celebrex® 400 mg once a day versus placebo and similar in size and duration to APC, does not appear to confirm this risk. This trial has also now been stopped based on the results of the ACP trial.

It is to be noted that the clinical trial data that have been submitted for all 3 currently registered COX-2 specific inhibitors (valdecoxib (Bextra®), etoricoxib (Arcoxia®) and celecoxib (Celebrex®, Onsenal®) are for durations of less than 33 months as compared to the APC trial and the Vioxx (rofecoxib) APPROVe trial (which was terminated in Oct 04 due to increased risk of CV events). This is in-line with internationally accepted guidelines for data submission for registration of drugs intended for long-term treatment of non-life threatening conditions.

Prior to this new development, previous studies on Celebrex®, including clinical trials and epidemiological studies have not suggested the same risk as in the APC trial. For example, in the Celecoxib Long Term Arthritis Safety Study (CLASS), in which 8,000 patients were randomised in a comparison of Celebrex® 400 mg twice daily to ibuprofen or diclofenac for the treatment of osteoarthritis and rheumatoid arthritis and followed up for approximately one year, did not reveal a difference in CV risk. Another COX-2 specific inhibitor, valdecoxib (Bextra®) has recently been shown to have an increased risk of CV events when used in the management of pain in patients following coronary artery bypass grafting (CABG).

The US FDA has also noted that it is not known whether other non-steroidal anti-inflammatory drugs (NSAIDs) pose a similar risk as similar long-term studies of other products in the class of NSAIDs other than COX-2 inhibitors have not been done.

HSA has proceeded to obtain relevant data on these and other ongoing Celebrex® trials from the company in order to determine the significance of these findings. We will also be closely monitoring the regulatory actions taken by other regulatory agencies to determine the appropriate regulatory action. HSA will update our healthcare professionals on Celebrex® and this class of drugs in general when more information becomes available.

• In the light of recent information about CV risk associated with COX-2 inhibitors, starting with the Vioxx® worldwide recall, physicians are advised to exercise caution when prescribing COX-2 inhibitors to patients at risk of CV conditions.
  
  
• In view of the developing information, physicians are advised to review the risks and benefits of Celebrex® when prescribing the drug to individual patients. Alternative therapies could be evaluated taking into account individual patient needs and risk factors. If continued use of Celebrex® is assessed to be appropriate for the individual patient, HSA advises the use of Celebrex® at the lowest effective dose and any long-term use should be regularly reviewed.
  
  
• Physicians are referred to the December issue of the HSA's ADR News Bulletin for more information on COX-2 specific inhibitors in general:
  ADR News Bulletin Dec 2004 Vol. 6 No. 3 
  
  or the Product Safety Alert:
  17 Dec 04: COX2 inhibitors