Use with caution in patients with cardiovascular disease or renal dysfunction

On 30th September 2004, Merck Sharp and Dohme (MSD) made an independent decision to voluntarily withdraw Vioxx® worldwide.

The withdrawal was based on the findings of the APPROVe clinical trial, a multicentre, randomized, placebo-controlled, double blind 3-year study investigating the effects of 25 mg dose of rofecoxib on the recurrence of neoplastic large bowel polyps in 2,600 patients with a previous history of colorectal adenoma.

The trial was terminated prematurely at the 34th month due to an increased incidence of cardiovascular (CV) events in patients taking Vioxx®: 25 patients taking placebo versus 45 patients taking Vioxx® experienced a confirmed serious thrombotic event (including myocardial infarction and stroke). The absolute event rates were approximately 3 per 400 patient-years for placebo and 6 per 400 patient-years for Vioxx®, i.e. an absolute increase of approximately 3 thrombotic events per 400 patient-years of treatment. The difference in event rates was only apparent after 18 months of continuous intake of Vioxx®.

At the time of withdrawal, Vioxx® was approved for use in over 80 countries. It was registered in Singapore in 1999 at about the same time as in the United States and the United Kingdom. The risk of CV events was not detected in the pre-marketing clinical trials.

There are 3 other cyclooxygenase-2 (COX-2) specific inhibitors currently registered in Singapore, namely celecoxib (Celebrex® and Onsenal®, Pfizer), valdecoxib (Bextra,® Pfizer) and etoricoxib (Arcoxia®, MSD). All except Onsenal® are indicated for the treatment of osteoarthritis, rheumatoid arthritis and acute pain. Onsenal® is approved for the regression and reduction of adenomatous polyps in patients with familial adenomatous polyposis. These 3 drugs are registered in many countries including the United Kingdom and Australia and were approved for marketing as they fulfilled the requirements for drug registration based on internationally accepted guidelines. They have different chemical structures, although they work similarly by selectively inhibiting the COX-2 pathways.

With this recent finding from the APPROVe study, a potential safety concern has been raised as to whether the increased thrombotic events seen with Vioxx® could be a class effect. Mechanistically, COX-2 specific inhibitors are known not to affect platelet function compared to non-selective NSAIDs which have potent and sustained antiplatelet effects that might provide cardioprotective benefits. In addition, because these drugs decrease systemic prostacyclin production without affecting platelet thromboxane production, there is a theoretical possibility that there may be an increase the risk of a prothrombotic event.

Although the clinical trial data that have been submitted for the existing 3 COX-2 specific inhibitors were of durations less than 3 years as compared to the APPROVe trial, based on the available evidence to-date, there is insufficient information to make a conclusive CV statement of these existing COX-2 inhibitors. With this new information of increased CV risk to Vioxx®, the affected companies are embarking on or currently have clinical trials that will go on for a longer duration, in order to ascertain the safety profile of these products. The US FDA will be holding an advisory committee meeting in February 2005 to review the safety issues of COX-2 inhibitors including defining the type of data that it will require before approving subsequent entrants in the class.

HSA will closely monitor the international regulatory developments on COX-2 specific inhibitors which will take place over the next few months as well as closely monitoring the local ADRs to these drugs. Healthcare professionals will be updated on the regulatory position of HSA when more confirmatory evidence is found.

• Caution must be exercised when prescribing these drugs to patients at risk of CV conditions, such as patients with a history of hypertension or ischaemic heart disease. Patients should be advised to see their physician in the event of any worsening of heart disease symptoms.
  
  
•  COX-2 inhibitors should be used with caution in patients with renal dysfunction or in the elderly as they have been reported both locally and worldwide to cause serious adverse effects, including acute renal failure. When used in these patients, the lower recommended dose should preferably be prescribed and patients should be closely monitored.
  
  
• Physicians are reminded that COX-2 specific inhibitors do not offer CV protection and are not substitutes for aspirin for prophylaxis of CV diseases because of their lack of effect on platelet function.
  
  
• For more information on the use of COX-2 inhibitors, please refer to the “Guidance on use of COX-2 inhibitors” developed by the UK National Institute for Clinical Excellence at  http://www.nice.org.uk/pdf/coxiifullguidance.pdf