Published: November 2004
ADR update

COX-2 Inhibitors - Where to From Here?

Prescriber Update 25(2): 17-18
November 2004

Medsafe Editorial Team

What happened and why?

On 1 October 2004, Merck Sharp & Dohme (MSD) announced their decision to withdraw Vioxx® (rofecoxib) worldwide due to concerns about its cardiovascular safety.  These concerns arose from a three-year study (known as APPROVe*) undertaken to evaluate the efficacy of rofecoxib (25mg) versus placebo in preventing the recurrence of colorectal polyps.  During this study, it was noted that the risk of cardiovascular adverse events such as myocardial infarction and cerebrovascular accidents was doubled in patients using rofecoxib for more than 18 months, compared to patients using placebo.

At the time of its withdrawal, Vioxx was approved for use in over 80 countries.  It was registered in New Zealand in January 2000, and in the United States of America and United Kingdom in 1999.  The risk of cardiovascular events was not detected in the pre-marketing clinical trials.

Why did the cardiovascular events occur?

There are a number of plausible mechanisms that may explain why rofecoxib appears to be associated with an increased risk of cardiovascular events.  However, it is unclear which is more likely to be responsible.  A prothrombotic or atherogenic effect may be involved.

What has Medsafe done?

From the date of first marketing, Medsafe (and other regulatory agencies around the world) have collected and analysed adverse reaction reports for rofecoxib and the other COX-2 inhibitors as part of standard post-marketing monitoring practice.  In December 2000, both rofecoxib and celecoxib were added to the Intensive Medicines Monitoring Programme (IMMP); the reason being that these two medicines were the first in a new class of COX-2 specific anti-inflammatories.

In New Zealand, the Medicines Adverse Reactions Committee (MARC) had previously reviewed all significant data but found that the evidence for an association between any of the COX-2 inhibitors and increased cardiovascular events was inconclusive.  The local pattern of use indicated that users of COX-2 inhibitors were older, had other co-morbidities and were often on multiple medicines that could have increased their risk of this type of event.  Medsafe and MARC have also monitored and reviewed published literature on adverse events in general with the COX-2 inhibitors.

What is Medsafe doing now?

Medsafe will be asking MSD to supply full data on the APPROVe study, along with any other data not previously available.  Sponsors of other COX-2 inhibitors will also be asked for updated safety data, including details of any studies underway.  Medsafe will additionally be liaising with other regulatory authorities, such as the TGA (Australia), FDA (United States of America) and Health Canada (Canada).  Published data on cardiovascular events for all the COX-2 inhibitors, along with New Zealand case reports of adverse reactions and any other available unpublished data, will be reviewed by the MARC.  Advice will be provided to prescribers once analysis of all the evidence is completed.

What about the other COX-2 inhibitors?

At this stage, there is insufficient information available to comment on the cardiovascular safety of the other COX-2 inhibitors (i.e. celecoxib, etoricoxib, meloxicam, parecoxib and valdecoxib).  Medsafe will be asking the MARC to determine whether the risk of cardiovascular events is similar for the other COX-2 inhibitors, in comparison to rofecoxib.

What should prescribers do?

As all stock of rofecoxib has been removed from New Zealand, prescribers will need to discuss alternative options with their patients.  This requires consideration of both the adverse event profile of possible substitutes (such as NSAIDs or other COX-2 inhibitors) and patients' individual risk factors for gastrointestinal and cardiovascular harm.  In some patients paracetamol may be an effective alternative.

Prescribers can assist in monitoring the safety of all COX-2 inhibitors by reporting adverse events to the Centre for Adverse Reactions Monitoring (CARM) in Dunedin.  Reporting forms are available on both the Medsafe and CARM web sites.

Where to from here?

Once Medsafe has obtained all the necessary data and the MARC has completed its analysis, advice will be promulgated to prescribers.  It is intended that this advice will take into account that issued by other countries.  In the interim, the following additional information is available:

* Adenomatous Polyp Prevention on Vioxx