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Strong warning on COX-2 inhibitors

22 February 2005

Ministry of Health issues strong warning on COX-2 inhibitors

THE MINISTRY of Health says the increased risk of heart attack and stroke (cardiovascular events) outweighs the benefits of COX-2 inhibitors for the general population.

It is advising people who are at high risk of cardiovascular events to see their doctor to discuss stopping treatment with COX-2 inhibitors immediately. Others taking the medicines but not at high risk should discuss cessation of the COX-2 inhibitor at their next scheduled GP appointment and consider alternative treatment options.

"We don't have enough information yet to quantify the risk associated with each of the five Cox-2 inhibitors currently available in New Zealand," Ministry spokesman Dr Stewart Jessamine said today.

"But our preliminary conclusions are that all COX-2 inhibitors may increase the risk of developing a heart attack or stroke to some degree in some patients."

Dr Jessamine said those at high risk were patients with a previous history of heart attack or stroke; a strong family history of heart disease; a history of diabetes, smoking, hypertension, or who are on treatment for high cholesterol.

Dr Jessamine, Principal Medical Advisor with Medsafe, the Ministry of Health’s medicines regulator, said Medsafe had reviewed the safety of all COX-2 inhibitor medicines. The review followed last October's recall of one of these medicines, Vioxx, after international findings that its use was associated with an increased risk of heart attack and stroke.

The Medsafe review considered data on the safety and efficacy of each COX-2 inhibitor from the published literature and that submitted by the pharmaceutical industry in support of their products.

"Unfortunately despite reviewing extensive amounts of data, there is still not enough information to quantify the risk associated with each of these medicines, or to determine which patients are at increased risk or whether aspects of treatment such as dose or duration of use affect the degree of risk," Dr Jessamine said.

"While there is uncertainty about the degree of risk posed by each medicine, on the basis of the evidence available to date Medsafe’s opinion is that the possible increased risk of heart attack and stroke outweigh the benefits of COX-2 inhibitors for the general population. At least 60,000 people are estimated to have taken a COX-2 inhibitor in the past year, however, Medsafe do not have prescribing data and so cannot determine the actual number of patients using these medicines. ”

Medsafe is seeking further information from the pharmaceutical industry and the published literature before making a final decision on the safety of these products. The Medicines Adverse Reactions Committee will discuss Medsafe's preliminary conclusions and any further data published or submitted on the safety of the COX-2 inhibitors at its March 2005 meeting. Any FDA or European regulatory agency findings made in the interim will also be considered at this meeting.

"To reiterate: in the interim our advice is this," Dr Jessamine said. · Patients who are being treated with a COX-2 inhibitor and who are at high risk of developing a cardiovascular event such as: a previous history of heart attack or stroke, who have a strong family history of heart disease, or have a history of diabetes, smoking, hypertension, or who are on treatment for high cholesterol should see their doctor to discuss stopping treatment immediately.

All other patients being treated with COX-2 inhibitor medicines should discuss alternative treatment options with their GP at their next scheduled appointment.

BACKGROUND MATERIAL

What are COX-2 inhibitors? COX-2 inhibitors are a relatively new type of anti-inflammatory medicine used to relieve pain, swelling and inflammation. Pain and inflammation are mediated in the body by a number of signal chemicals; several of these chemicals are created by the action of the enzyme cyclo-oxygenase (COX) on the chemical arachadonic acid. There are two forms of the COX enzyme, COX-1 and COX-2. Different proportions of COX are found in different tissues, and inhibiting this enzyme produces different effects on each tissue where the enzyme is blocked.

Older anti-inflammatory agents predominately block the COX-1 form of the enzyme and in addition to producing relief from pain and inflammation, can cause stomach ulceration by blocking the effect COX-1 action has in producing protective mucous in the stomach. The newer COX-2 medications produce a lesser effect on COX-1 and therefore are thought to be more specific for pain and inflammation and less likely to cause gastrointestinal side effects. The COX-2 inhibitor medicines listed below are approved for the treatment of arthritis and acute pain, and in the case of celecoxib as a treatment for a rare condition that causes polyps on the bowel.

Why do COX-2 inhibitors increase the risk of heart attacks or strokes? COX-2 inhibition is thought to increase the risk of heart attacks and strokes through the changes it produces to substances called prostacyclins, prostaglandins and thromboxane. These three substances are involved in the initial stages of blood clotting and the body’s response to blood clots. COX-2 inhibition upsets the balance between these substances, by increasing the levels of the substances that activate components of blood called platelets to form clots and decreasing the level of other substances that prevent platelet clot formation and respond to the creation of small clots on the walls of arteries. When blood clots lodge in the arteries of the heart, heart attacks can occur. Similarly, blood clots in the arteries of the brain may cause a stroke.

Why did Medsafe conduct a review of the COX-2 inhibitors? Following the voluntary recall last October of the COX-2 inhibitor Vioxx due to the finding that use of this medicine was associated with an increased risk of developing a heart attack or stroke, Medsafe has been conducting a review of the safety of all COX-2 inhibitors medicines. This review has considered data on the safety and efficacy of each COX-2 inhibitor from the published literature and data submitted by the pharmaceutical companies that market COX-2 inhibitor products in New Zealand.

Can COX-2 Inhibitors be stopped suddenly? Unlike many other medicines, the COX-2 inhibitor medicines can be stopped suddenly without ill effect. However patients may need to take some other painkiller or anti-inflammatory medicine to manage the return of symptoms. A number of alternatives treatments are available. Medsafe has advised doctors to discuss the various alternatives with patients before starting other medicines. All General Practitioners should have recently received a publication from the Best Practice Advocacy Group (BPAC) describing options and strategies for managing pain and inflammation. This document includes advice on managing pain in patients with gastric ulcer disease.

Which COX-2 inhibitors are available in NZ? Celecoxib (brand name: Celebrex) Etoricoxib (brand name: Arcoxia) Meloxicam (brand name: Mobic) Parecoxib (brand name: Dynastat) Valdecoxib (brand name: Bextra)

What alternative anti-inflammatory agents are available? Alternatives anti-inflammatory agents include: Diclofenac (brand names: Apo-Diclofenac, Apo-Diclo SR, Voltaren) Ibuprofen (brand names: I-Profen, Brufen, Brufen Retard) Sulindac (brand names: Clinoril, Daclin) Tiaprofenic acid (brand names: Surgam, Surgam SA) Ketoprofen (brand names: Orudis, Oruvail) Naproxen (brand names: Naxen, Naprosyn SR, Synflex) Tenoxicam (brand names: Tilcotil) Piroxicam (brand names: Piram D)

What is Medsafe doing next? Medsafe is seeking further information from the published literature, other medicines regulators and the pharmaceutical companies who distribute COX-2 inhibitor medicines. The Medicines Adverse Reactions Committee will discuss this information at its next meeting in March 2005. Once this has occurred, Medsafe will make a final decision on the safety of the COX-2 inhibitors.

What are other countries doing? The Australian Therapeutics Goods Administration, the European Medicines Agency and an advisory committee to the United States Food and Drug Administration have recently completed reviews of the safety of COX-2 inhibitors. All three agencies reached similar conclusions to Medsafe that increased cardiovascular risk is a class effect and is present in all COX-2 inhibitor medicines.

The preliminary advice issued by the Australian and European regulators however, differs from that proposed by Medsafe. The Food and Drug Administration are yet to make a statement on this issue. In Medsafe’s opinion, the prescribing, funding and consumer environment in New Zealand differs from the Australian and European environments and warrants a more cautious approach.

For example of the six COX-2 inhibitors that have Ministerial consent to market in New Zealand, five are currently actively marketed and none are government-funded. Medsafe therefore has only limited information on the types or numbers of patients being prescribed these medicines. In Australia, while the same six medicines are approved for use, only three of the group are marketed, and two are government-funded. Prescribing data available to the TGA allows it to ascertain information on the numbers of patients using these medicines and the doses being prescribed.

In addition, direct-to-consumer advertising of prescription medicines is prohibited in both Australia and Europe.

Links to other material:

Europe: EMEA announces regulatory action on COX-2 inhibitors – 17 Feb 2005 http://www.emea.eu.int/htms/hotpress/d6275705.htm

EMEA updated Questions and Answers on COX-2 inhibitors – 17 Feb 2005 http://www.emea.eu.int/pdfs/human/press/pr/6297805en.pdf

UK: MHRA issues updated on advice of the safety of selective COX-2 inhibitors – 17 Feb 2005 http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ddl cox2170205.pdf

New Zealand: Minutes of Medsafe meeting with MARC Chair – 11 Feb 2005: www.medsafe.govt.nz/Profs/adverse.htm

Australia: TGA media statement – 10 Feb 2005 http://www.tga.gov.au/media/2005/050210_cox2.htm

Additional information for doctors and pharmacists – 14 Feb 2005 http://www.tga.gov.au/media/2005/050214_cox2.htm

ENDS

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