Thousands of Canadians who rely on a new generation of painkillers have been left in medical limbo after the worlds biggest drug maker warned yesterday that yet another blockbuster medication may pose serious safety risks.
Less than three months after the popular arthritis and pain medication Vioxx was pulled off the market for increasing the risk of heart attacks and strokes, Pfizer Inc. announced that Celebrex, the drug billed as the safe alternative, had been suspended from use in a clinical trial after it too was found to raise the risk of cardiovascular problems and deaths when taken at doses of more than 400 mg a day.
For this reason, Health Canada said last night it had withdrawn Pfizers approval to sell the drug to treat a rare genetic colon disorder called familial adenomatous polyposis, a condition for which Celebrex has been prescribed at high doses for long-term use. Celebrex had been shown to reduce the progression of colon polyps in FAP.
Canadians filled nearly three million prescriptions for Celebrex last year. The drug has been taken by an estimated 26 million people worldwide, usually for arthritis, but also for pain linked to everything from sprains to tendinitis. Many have switched to the medication since Vioxx, made by Merck & Co., vanished from pharmacies after Sept. 30.
At the same time, the New England Journal of Medicine released a report yesterday that calls for clinicians to stop prescribing Pfizers Bextra, another popular new-generation painkiller, on the grounds that it too may increase cardio-toxicity. Doctors from the Vanderbilt University School of Medicine write that the reservations about Bextra represent a potential imminent hazard to public health and thus require action.
Together, the new developments are fueling growing concern that this entire new class of anti-inflammatory medications known as cox-2 inhibitors, which were initially touted as wonder drugs of the bio-tech age, may simply be bad news for the heart. They are also bound to raise further concern about the regulations that bring new drugs to market and how well they're monitored once they hit the shelves.
Health Canada itself acknowledged in a statement yesterday that there has been a lack of published safety data regarding use for longer than one year of selective cox-2 inhibitor drugs, including Bextra, Mobicox and Celebrex, whose generic name is celecoxib.
Based on the information available, Health Canada said there may indeed be an increased cardiovascular risk linked to these medications, particularly in patients who have other heart-disease risk factors, such as high blood pressure, high cholesterol, smoking or diabetes.
Health Canada is now urging people who take Celebrex at relatively high doses of between 400 and 800 milligrams a day to discuss alternatives with their doctors and whether the risk of cardiovascular side effects outweigh the benefits.
Just last month, Health Canada had Pfizer turn over further clinical trial data related to Celebrex after health professionals linked the drug to the deaths of 20 Canadian patients in recent years. As well, in 2002 Health Canada required that Celebrexs label include a warning that the drug could increase the risk of congestive heart failure.
Despite these reservations, Health Canada spokesperson Jirina Vlk noted that in the end these products work for roughly 98 per cent of the people taking them.
Toronto resident Christina Scicluna, a 22-year-old student volunteer with the Arthritis Society of Canada, is among those who plan to wait patiently for further investigations into Celebrex. Ms. Scicluna, who has been treated for rheumatoid arthritis since she was 18, has been taking 400 milligrams of Celebrex a day since Vioxx was pulled. Without Celebrex, her options are bleak, she said.
To find out that something else that is working for me might also be pulled off the market is stressful, said Ms. Scicluna, who, without drugs, finds the pain too excruciating to walk, or even write. But I am 22 and the long-term effects of taking medication really troubles me.
The U.S. National Institutes of Health said in a statement that it suspended the use of Celebrex after discovering that patients taking the drug at daily doses greater than 400 mg during a long-term cancer study faced a 2.5-fold increase of major fatal and non-fatal cardiovascular events, compared to those taking a placebo. Health Canadas Vlk noted that the increase in risk was 3.4-fold when the dose rose to 800 milligrams a day.
The study, conducted by the National Cancer Institute, had been investigating whether Celebrex could prevent colorectal cancer in 2,000 patients who had had a precancerous growth removed. The trial, which included patients in Canada, was to have lasted until spring 2005.
But signs of heart risks linked to the drug became apparent in September, and on Thursday night, the drug company heard the numbers.
Pfizer, whose market value dropped $24-billion (U.S.) with the news, has now promised to investigate the issue further. It also plans a large trial to assess Celebrex in osteoarthritis patients already at high risk of cardiovascular problems.
These clinical trial results are new, Pfizer chairman and chief executive officer Hank McKinnell said. Pfizer is taking immediate steps to fully understand the results and rapidly communicate new information to regulators, physicians and patients around the world.
The circumstances in the Celebrex case are eerily similar to those that led the downfall of Vioxx. It too was being tested in a colon cancer trial when it was found to double the risk of heart attacks and strokes. The results prompted Merck & Co. to halt the trial and remove Vioxx from the market worldwide, a move that many say regulators should have demanded years earlier.
But doctors and researchers agree the case with Celebrex is not as clear-cut. For one, the drug was linked to higher cardiovascular risks when tested at doses of 400 to 800 milligrams daily. Usually, doses of less than 400 mg a day are prescribed.
Muhammad Mamdani, a senior scientist with the Institute for Clinical Evaluative Sciences in Toronto, has for the past three years been investigating the safety of cox-2 drugs, which are named for their power to shut off the cyclo-oxygenase-2 enzyme that contributes to pain and swelling.
During that time, Dr. Mamdani and his colleagues found Celebrex seemed much gentler on the heart than either Vioxx or the older anti-inflammatory drugs such as ibuprofen or naproxen. I am surprised at these results, he said. When used in reasonable doses, Celebrex really didn't seem to increase the risk of cardiovascular problems.