INDEPTH: DRUGS
Vioxx, Celebrex: Concerns over popular arthritis drugs
CBC News Online | December 17, 2004
They burst onto the scene in 1999 – a new class of drugs that promised wonders for sufferers of arthritis. They were called COX-2 inhibitors and tests suggested that people who had trouble tolerating traditional arthritis drugs could handle these drugs better.
A bottle of Vioxx, right next to a bottle Pfizer's Celebrex at a pharmacy. (AP Photo/Mary Altaffer) |
The problem with most arthritis drugs before Celebrex and Vioxx were approved for sale was that some people suffered serious stomach problems from traditional non-steroidal anti-inflammatory drugs (NSAIDs). For some people, too much Aspirin or ibuprofen could lead to bleeding or ulcers.
NSAIDs go after two enzymes in the body: one plays a role in causing arthritis pain and swelling (COX-2); the other protects the lining of the stomach (COX-1).
Traditional NSAIDs attack both enzymes, which means they can cause damage to the lining of the stomach. But drugs like Celebrex, Vioxx, Bextra and Mobicox were designed to target only the enzyme responsible for pain and inflammation. In theory, they would go after the enzyme that caused the pain and inflammation while leaving the lining of the stomach alone.
When the drugs were launched, they were accompanied by claims of far fewer gastrointestinal problems than traditional arthritis drugs. Within months of its launch in Canada, Celebrex was the top-selling prescription NSAID in the country.
CBC-Television's Marketplace raised questions about Celebrex in October 2000. By then, Health Canada had received hundreds of reports of serious adverse reactions to Celebrex – including 70 cases of stomach bleeding and 10 deaths.
In May 2002, Health Canada issued the first of its warnings about COX-2 inhibitors after a large clinical trial showed that Celebrex was no better than other arthritis drugs in terms of avoiding gastrointestinal side-effects.
The trial compared patients taking Celebrex with patients taking ibuprofen and Voltaren (also known as diclofenac).
"This clinical trial has shown that there is in fact no difference between the three drugs alone when it comes to gastrointestinal illness," Ryan Baker of Health Canada said when the warning was issued.
The trial did show there was a slightly lower risk comparing Celebrex patients and those on ibuprofen.
Pfizer (Celebrex) and Merck (Vioxx) stood by their arthritis drugs. Vioxx remained an important drug for Merck, its second-biggest earner with annual global sales of $2.5 billion in 2003. That represented 11 per cent of the company's $22.49-billion in revenue for that year. Two million people around the world were taking Vioxx.
Celebrex pulled in $2.29 billion in worldwide sales in 2003. But prescriptions for it surged in October 2004, after Merck pulled Vioxx off the market. The decision to withdraw Vioxx came after research showed the drug could increase the risk of heart attacks and strokes.
Merck said clinical trials showed heart conditions and cardiovascular complications began 18 months after patients started taking Vioxx, compared to those who took dummy pills.
The goal of the three-year study was to show that a 25-milligram dose of Vioxx prevented recurrence of polyps in the colon and rectum. Polyps can sometimes become cancerous.
"Although we believe it would have been possible to continue to market Vioxx with labelling that would incorporate these new data, given the availability of alternative therapies and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take," said Ray Gilmartin, Merck's chief executive officer, in a statement.
Within a week, a commentary in the New England Journal of Medicine called on drug companies to prove that their COX-2 inhibitors are safe.
With Vioxx off the market, prescriptions for Celebrex in Canada shot up by 38 per cent in October – more than 100,000 new prescriptions for the drug.
On Dec. 9, 2004, the U.S. Food and Drug Administration required new warning labels for Bextra, alerting patients to possible heart and blood clotting problems when the drug is used by patients who have just had heart bypass surgery. In less than a week, Health Canada followed suit.
On Dec. 17, 2004, Pfizer announced a long-term study on Celebrex also suggested an increased risk of heart attack. The findings came in one of two long-term cancer prevention trials, while the other trial showed no increased risk.
In the study, Pfizer was using doses of Celebrex up to twice as high as those currently recommended for rheumatoid arthritis patients.
At those doses, cancer patients involved in the new trial were experiencing "an approximately 2.5-fold increase in their risk of experiencing a major fatal or non-fatal cardiovascular event compared to those patients taking placebo," Pfizer said in a statement posted on its website.
But Pfizer did not follow Merck's lead in pulling the drug off the market. The company says the study that found an increased risk of cardiovascular problems is not consistent with other studies Pfizer and other companies have accumulated over time.
"Celebrex is an important medicine that provides necessary pain relief to many patients," the company said on its website. "Patientsshould discuss appropriate treatment options with their healthcare professionals. Physicians should factor this new information as well as ulcer risks and gastrointestinal bleeding seen with traditional NSAIDs, into their prescribing decision."
In the wake of the Pfizer announcement, The New England Journal of Medicine posted a letter from three American researchers, who called for an end to the prescribing of Bextra – "except in extraordinary circumstances." The researchers cited the studies that led to the new warning labels ordered by the FDA and Health Canada.
Meanwhile, queries put through Canada's Adverse Drug Reaction Database have shown 456 serious adverse reactions to Celebrex up to April 2004. Of those, 76 were related to cardiovascular/ cerebrovascular (heart attack/stroke) problems. Of the 456 total serious reactions connected to Celebrex, there were 30 deaths. Fourteen of those deaths were from heart attack or stroke.
Details on reports of adverse reactions connected with COX-2 inhibitors
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