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Expanded information on Cox-2 inhibitors for doctors and pharmacists (amended*)
*This amended version replaces the version placed on the TGA website on 10 February 2005. An error about the relationship of parecoxib to valdecoxib has been corrected.
The Therapeutic Goods Administration (TGA) has introduced new measures on the prescribing of anti-arthritis drugs known as Cox-2 inhibitors following the findings of a review into the safety of this family of medicines.
In September last year the popular arthritis drug, Vioxx, was withdrawn from the market world wide because medical trials had shown a significant increased risk of heart attacks and strokes.
In response, the TGA undertook urgent evaluations of new information provided by the sponsoring pharmaceutical companies of all other registered Cox-2 inhibitor drugs.
The results of this review were considered by the Australian Drug Evaluation Committee (ADEC) which made a number of recommendations to restrict the use of these drugs in Australia.
As a result, the TGA will immediately require manufacturers of Cox-2 inhibitors to place new highlighted explicit warnings in product information about the increased risk of cardiovascular adverse events from this group of drugs. The new warning statements are to be highlighted with a black boxed margin.
The TGA is also advising people who are taking more than 200mg a day of celecoxib (Celebrex) or more than 15 mg a day of meloxicam (Mobic; Movalis) to review their treatment regime with their doctors
The TGA believes that most Australians using these drugs will be taking low doses that already meet this dosage advice, but some patients, particularly with rheumatoid arthritis or a rare bowel condition, may be taking 400 mg or 800 mg of celecoxib a day and some patients with arthritis may be taking more than 15 mg of meloxicam a day.
This recommended dose reduction may result in some patients with arthritis having increased symptoms but the review of Cox-2 inhibitors clearly indicated there is an increased risk of heart attacks and strokes with high doses of these drugs.
ADEC reviewed evidence of six drugs in the Cox-2 inhibitor family, all of which were considered to be have risks associated with their use.
It determined that the exact size of the risk and the exact duration of therapy associated with increased risk are still unknown, and so have recommended that Cox-2 inhibitors should be prescribed only when other treatments cannot be tolerated or have caused serious adverse effects.
In addition celecoxib and meloxicam should not be prescribed for patients with increased risks of cardiovascular events, such as heart attacks, and treatment should be limited to the shortest time needed.
Concerning celecoxib, the Committee took into account the results of a study of celecoxib 800 mg a day in low cardiovascular risk patients which showed an increased risk of cardiovascular events. The results of studies of 400 mg a day of celecoxib in low cardiovascular risk patients are conflicting with one study at this dose level finding an increased risk.
On the other hand, several recently published papers describing observational studies of patients using large linked medical record databases in North America have not reported an increased myocardial infarction risk with celecoxib. Dose analysis was not undertaken in all studies but it is likely that a large majority of patients were taking 200 mg/day or less. Such observations are consistent with the preliminary results of an Australian case-control study, the results of which were made available to ADEC. An increased risk of acute coronary syndrome was not found for the patients that were studied. Very few of these Australian patients were taking more than 200 mg a day of celecoxib.
Concerning meloxicam, there are theoretical grounds for regarding the drug as having reduced cardiovascular risks. The drug has less selective Cox-2 inhibition than celecoxib or rofecoxib. Clinical study data are more meagre, with most studies limited to no more than six months duration. The Committee notes that a Prescription Event Monitoring study in the UK and an observational study in Quebec, Canada, provided reassurance that the cardiovascular risk at up to 15 mg is acceptable. ADEC recommended that further research be conducted.
The new requirements reinforce and extend advice given to Australian heath care professionals in the Australian Adverse Drug Reactions Bulletin, October 2003, and repeated in December 2004.
The TGA has also accepted a number of other recommendations of ADEC and has given notice to the relevant companies:
- it is proposed to cancel the registration of the drug parecoxib (Dynastat) because of the risk of cardiovascular events. Dynastat is marketed in Australia and is approved as a single dose at the time of surgery to reduce post-operative pain. Parecoxib is converted to valdecoxib in the body;
- it is proposed to withdraw the indication of management of arthritis of the drug valdecoxib (Valdyne, Dynoral - known in some countries as Bextra). Valdecoxib has not been marketed in Australia. Valdecoxib has been associated with an increased risk of cardiovascular events in cardiac by-pass graft patients. The use of Valdecoxib for 5 days as an analgesic in patients without increased cardiovascular risk will remain.
- it is proposed to greatly limit the approved uses of two other Cox-2 inhibitors which have not yet been marketed in Australia. They are etoricoxib and lumiracoxib. In both instances, ADEC was not sufficiently assured of the safety of these drugs for anything other than short term use in patients without increased cardiovascular risk.
Concerning parecoxib and valdecoxib, ADEC noted reports of two published studies in which valdecoxib alone for 14 days and parecoxib followed by valdecoxib for 10 days were associated with increased risk of cardiovascular events in patients undergoing coronary artery bypass graft surgery. The Committee was not assured from other available data that the safety of parecoxib in other surgical patients or the safety of valdecoxib, other than when used for short periods in patients without cardiovascular risk, had been studied adequately.
People who are concerned about their use of Cox-2 inhibitors should discuss their treatment with their medical practitioner.
Dr John McEwen
Principal Medical Adviser
14th February 2005