NEWS - Australia takes tough stance on COX-2 inhibitors

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Australia takes tough stance on COX-2 inhibitors

Rheumawire

Feb 11, 2005

Zosia Chustecka

Woden, Australia - The Australian medicines watchdog, the Therapeutic Goods

Administration (TGA), has introduced tough new measures that will curtail

the use of COX-2 inhibitors [1,2]. The announcement, made yesterday, follows

an urgent review of this class of drugs by the Australian Drug Evaluation

Committee (ADEC) after the withdrawal of rofecoxib (Vioxx, Merck & Co) in

September 2004.

The results of that review are a number of new recommendations that will

restrict the use of these drugs in Australia. For 2 productscelecoxib

(Celebrex, Pfizer) and meloxicam (Mobic, Movalis, Boehringer Ingelheim)the

regulators have demanded that both products carry, with immediate effect, an

explicit black-box warning about the increased risk of cardiovascular

adverse events from this group of drugs.

In addition, the TGA has recommended that only lower doses be used. It is

advising any patients who are taking more than 200 mg daily of celecoxib or

15 mg daily of meloxicam to review treatment with their doctor. TGA

principal medical adviser Dr McEwen says most Australians using these

drugs are on these low doses, but there are patientsparticularly those with

rheumatoid arthritis (RA) or a rare bowel conditionwho may be taking 400 mg

or 800 mg celecoxib daily, and some patients with arthritis may be taking

more than 15 mg meloxicam daily. " Unfortunately, this recommended dose

reduction may result in some patients with arthritis having increased

symptoms, but the review of the COX inhibitors clearly indicated there is an

increased risk of heart attacks and strokes with high doses of these drugs, "

McEwen commented.

A third product marketed in Australia, the injectable parecoxib (Dynastat,

Pfizer), is currently approved as a single dose given at the time of surgery

to reduce postoperative pain. The regulators propose to cancel this

registration because of the risk of cardiovascular events.

The other COX-2 inhibitors haven't been launched in Australia yet and now

look as if they will be very restricted, if they reach the market at all.

For both etoricoxib (Arcoxia, Merck & Co) and lumiracoxib (Prexige,

Novartis), the statement released to the press says, " ADEC was not

sufficiently assured of the safety of these drugs for anything other than

short-term use in patients without increased cardiovascular risk. " For

valdecoxib (Bextra, Pfizer), which is converted to parecoxib in the body,

the regulators say that they will consider its use for 5 days as an

analgesic in patients without increased cardiovascular risk. However, it

will withdraw the indication of management of arthritis, because valdecoxib

has been associated with an increased risk of cardiovascular events in

coronary-artery-bypass-graft (CABG) patients.

ADEC chair Prof Tattersall (University of Sydney, Australia) said

that the committee had reviewed evidence for all 6 drugs in the COX-2

family, and all were considered to have risks associated with their use.

" The exact size of the risk and the exact duration of therapy associated

with increased risk are still unknown, so we have recommended that COX-2

inhibitors should be prescribed only when other treatments cannot be

tolerated or have caused serious adverse effects, " he commented. " 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, " he said.

For celecoxib, the committee says it took into account results from a study

showing an increased cardiovascular risk with 800 mg daily and 400 mg daily

(the APC study) but notes that there are conflicting results from other

studies with 400 mg that don't show an increased cardiovascular risk. Also,

it notes that several published papers describing large linked

medical-record databases in North America have not reported an increased

myocardial risk with celecoxib; dose analysis was not undertaken in all of

these studies, but it is likely that the large majority of patients were

taking 200 mg daily or less, according to ADEC. These observations are

consistent with the Australian experience so far, it adds. Preliminary

results from a national case-control study, in which few patients exceeded

this dose, don't show an increased risk of acute coronary syndrome, it

notes.

For meloxicam, there are theoretical grounds for regarding the drug as

having reduced cardiovascular risks, the committee comments, noting that it

is a less selective COX-2 inhibitor than celecoxib or rofecoxib. (In fact,

putting meloxicam into the same category of COX-2 inhibitors is rather

controversial, as there are many expertsespecially in the USwho say it does

not to fit into the same category, as it is selective only at lower doses

and loses this selectivity at higher doses; in some other countries, it is

regarded as a COX-2 preferential agent rather than a selective COX-2

inhibitor.)

However, the clinical data for meloxicam are " more meager, " ADEC comments,

with most stretching only to 6 months. But data collected from other sources

are reassuring, it says: a UK Prescription Event Monitoring Study and an

observational study from Quebec, Canada, have provided reassurance that the

cardiovascular risk at doses up to 15 mg is " acceptable. " Nevertheless, ADEC

recommended that further research be conducted.

The decisions on parecoxib and valdecoxib were made on the basis of 2 trials

in CABG patients that showed an increased cardiovascular risk. " 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. "

About 3 million people in Australia have some form of arthritis, and about

500 000 are taking COX-2 inhibitors, according to estimates in the

Australian [3]. The newspaper quotes the chief executive of Arthritis

Foundation of New South Wales, Philip Hopkin, as saying that he was not

surprised at the move. " These are very serious drugs, and I think it's

probably a good idea, " he says. The news will be particularly worrying to

patients who had moved onto another COX-2 inhibitor after being taken off

rofecoxib, he commented, but pointed out that there are other options, such

as acetaminophen (paracetamol) and other anti-inflammatories, as well as

alternative therapies such as glucosamine and fish oil.

Sources

Regulator takes tough action on arthritis drugs, February

10, 2005

Expanded information on -2 inhibitors for doctors and

pharmacists, February 10, 2005

Pirani C. Arthritis drugs to carry cardio health warnings.

Australian, February 11, 2005. Available at:

http://www.theaustralian.news.com.au/

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