Critics say millions of people were needlessly exposed to the risks of Bextra due to intense off-label promotion and advertising that boosted the painkiller to a position near the top of the list of the most widely prescribed drugs in US history.
Although a drug can only be marketed for specific indications approved by the FDA, doctors are allowed to prescribe a drug for any use regardless of whether it's approved for a diagnosis, and Pfizer spent a fortune convincing physicians to prescribe Bextra for unapproved uses.
In 2003, the number of prescriptions written for Bextra totaled 10.4 million. In the same year, the cost of promotions aimed at prescribing doctors reached $395.6 million, according to IMS Health, a pharmaceutical information and consulting company.
And the money doled out to influence doctors paid off. In 2003, IMS reported sales of Bextra totaled $935 million and in 2004, CNN Money Line said Bextra had sales of $1.3 billion. In 2004, 12.9 million prescriptions were filled in the US for Bextra.
According to the FDA, Bextra was approved for the treatment of pain associated with osteoarthritis, rheumatoid arthritis and dysmenorrhea (menstrual pain).
Yet two Pfizer sales representatives recently told ABC News Channel 7, Reporter Andrea McCarren in a TV interview, that they were told to promote Bextra for: "Heel pain, back pain, pain from orthopedic surgeries, any kind of pain."
"Going into hospitals getting in on pain protocols and that's completely illegal," the first sales rep said.
Another rep told Ms McCarren: "We were expected to sell it for pre-operative pain and post-operative pain, which is totally out of indication."
"And there is a huge amount of money that can be made for a drug that gets sold for that," the second rep said in the interview.
According to a May 2004 analysis conducted by Knight Ridder, half of all Bextra sold was prescribed for off-label uses.
In a March 2004 regulatory filing, Pfizer disclosed the company was under scrutiny by the US Justice Department over its off-label marketing of the drug for unapproved uses.
The worst part about the off-label marketing of Bextra, is that studies revealed over the past several years show the drug to be no better than other pain medications, as dangerous or more dangerous than other pain relievers, and the drug should never have been prescribed for any use. And worst of all, Pfizer knew it.
A report published in the December 3, 2005 British Medical Journal claims drugs like Bextra are just as harmful to the stomach as conventional anti-inflammatory drugs like aspirin, which debunks the main reason that drugs in this class were approved and over-prescribed to begin with.
According to the FDA web site accessed on January 24, 2006, under Special Warnings: "Bextra and all NSAID medications can cause stomach ulcers that bleed. The chance of this serious problem increases the longer you take Bextra, but it can also happen suddenly."
The FDA told consumers to call a doctor right away if you get:
• a burning stomach pain
• black bowel movements that look like tar
• vomit that looks like blood or coffee grounds
In addition, under "General Precautions" it warns: "Bextra and other NSAID medications can cause serious problems such as liver damage. Some of the warning signs of liver damage are nausea, vomiting, tiredness, loss of appetite, itching, yellow coloring of skin or eyes, "flu-like" symptoms and dark urine."
The FDA warned: "Bextra can cause fluid retention (holding of water in your body). Fluid retention can be a serious problem if you have high blood pressure or heart failure."
But none of this information is actually "new" news. Back on October 16, 2004, Dr Sandra Kweder, the FDA's then acting director of the office of new drugs, told the New York Times that Bextra had not been proved to be any better than older medicines at guarding against stomach bleeding and had not been proved to be any better at relieving pain than older drugs.
A little over a month later, on November 18, 2004, Dr David Graham, associate director of drug safety in the FDA, testified at a Congressional hearing on Vioxx and said, "I can tell you right now, there are at least five drugs on the market today that I think need to be looked at quite seriously to see whether or not they belong there."
When asked which drugs he was referring to, Dr Graham identified Accutane, Bextra, Crestor, Meridia and Serevent. He was later accused of providing "inflammatory" testimony.
Since he testified, it's worth mentioning that the FDA has either taken regulatory action, or has current action pending, on 4 out of the five drugs identified by Dr Graham.
And come to find out, on November 15, 2004, 3 days before Dr Graham gave "inflammatory" testimony, physicians were warned at the annual conference of the American Heart Association that Bextra might increase the risk of heart attack or stroke in patients who have had coronary artery bypass surgery (CABG), based on the results of a study conducted at the University of Pennsylvania.
Dr Garret Fitzgeral, a cardiologist and pharmacologist at the University, presented the results at the conference and described Bextra as "a time bomb waiting to go off."
The Pennsylvania study examined 5,930 subjects in twelve clinical trials and found patients who took Bextra experienced heart attacks and strokes 2.19 time more often than patients who received a placebo.
Less than one month after Dr Graham testified, the FDA issued a public health advisory on Bextra and said a change would be made in the product label to provide consumers with upgraded information about risks associated with the drug.
On December 9, 2004, the agency announced new information on Bextra side effects, and referred to another study, this one conducted by Pfizer, which included over 1,500 patients treated with Bextra after CABG, that showed an increased cardiovascular risk in patients treated with treated with the drug over those who received a placebo.
"Observed cardiovascular events," the FDA advisory said, "included thromboembolic events such as myocardial infarction (heart attack), cerebrovascular accident (stroke), deep vein thrombosis (blood clots in the leg), and pulmonary embolism (blood clot in the lung)."
"Bextra is not approved for use in the treatment of postoperative pain of any type;" the FDA pointed out in an advisory, "however, FDA believes that these new findings should be made available to healthcare professionals and patients, and the bolded warning specifically contraindicates Bextra for treatment of pain immediately following CABG," it said.
The FDA ordered a new label containing a "bold-faced warning" against prescribing and using Bextra for patients who have had heart bypass surgery, according to USA Today on December 10, 2004.
According to the FDA, Pfizer submitted the report to the agency on November 5, 2004. Yet, on October 16, 2004, the New York Times reported that Pfizer had warned doctors "yesterday" that one of its best-selling painkillers, Bextra, might increase the risk of heart attack or stroke in coronary artery bypass surgery patients, and the newspaper noted that the news came only 2 weeks after Vioxx was pulled off the market.
According to the Times, Pfizer said a study involving more than 1,500 patients showed that those who had undergone bypass surgery and had taken Bextra were at higher risk and that an initial study last year raised similar concerns in the same kinds of patients.
Dr Garret Fitzgeral criticized Pfizer, the Times said, for not making the information public more quickly since the company had completed the study in the spring.
Pfizer claimed it could not release the results sooner because it had to analyze the information.
On December 23, 2004, the New England Journal of Medicine reported that Bextra increased the risk of serious cardiovascular outcomes by a factor of approximately three.
And less than 2 months later, on February 14, 2005, the Associated Press announced a "new study has linked pain killers Vioxx, Celebrex and Bextra to increased cardiovascular risk, reinforcing findings of other trials that have already sparked concern over the safety of a popular category of drugs."
The study was conducted by WellPoint Inc., the nation's largest provider of health benefits and began after Vioxx was taken off the market. Researchers examined records for the period of January 2001 through June 30, 2004, on patients who were on the drugs for at least 18 months.
They studied the records of 7,232 patients over the age of 40 who were taking one of the three drugs and compared them with records of 629,245 people in the same age group who were not taking the drugs.
According to the AP, Bextra increased the risk of heart attack and stroke by 50 percent, and WellPoint reported finding no increase in cardiovascular events in patients taking traditional anti-inflammatory medications.
A little over a month later, on March 17, 2005, the New England Journal of Medicine published the results of a Pfizer clinical trial, confirming the 3-fold risk of stroke and heart attack.
In addition to heart, stroke and other problems listed above, Pfizer's 2004 third quarterly report filed with the Securities and Exchange Commission, said that a few patients treated with Bextra developed Stevens Johnson syndrome, which results when the immune system rejects a drug.
In October 2004, Pfizer sent a letter to doctors warning about the risks of SJS and said skin reactions had led to hospitalizations and deaths in a small number of patients.
As it turns out, the word "few" in the SEC report is a gross understatement. By November 2004, the FDA had already received 87 reports of cases of severe skin reactions associated with Bextra. Of the 87 patients, 36 required hospitalization and four patients died. Twenty involved patients with a known allergy to sulfa.
As always, it is important to consider that reports to the FDA on adverse events represent only one to 10% of the actual number of adverse reactions that occur.
In addition, seven people in Canada had reported severe skin reactions before Bextra was removed from the market, according to the December 17, 2005 Toronto Star.
Moreover, the word "severe" is much too mild an adjective to describe SJS. The disorder is more accurately described by Kristian Rasmussen and Amanda Slevinski Levin, Papantonio, et al P.A. who say: "Imagine a medical disorder where the body burns from the inside out. The skin scalds black and rots away. Sensitive area of the body, the eyes, mouth, anus and genitalia are massacred beyond function. The pain is so intense and uncontrollable, patients are medicated into an artificial coma for months at a time as the only means of relief. Welcome to Stevens-Johnson Syndrome, courtesy of you family medicine cabinet."
SJS warnings were placed on Bextra in November of 2002, approximately one year after the drug gained FDA approval, and stronger SJS warnings were issued by the FDA in February of 2003, and again by recommended label changes in August of 2004.
Despite Pfizer's knowledge of the SJS problem, the company never placed a black-box warning on the label until the FDA ordered one in December 2004, critics say because it would have killed direct to consumer marketing which would have been required to show the warning.
In addition to strengthening the previous warning about SJS, the "boxed" warning ordered by the FDA in December 2004, warned consumers that Bextra contains sulfa, and patients with a history of allergic reactions to sulfa may be at a greater risk of skin reactions.
The FDA allowed Bextra to remain on the market until April 7, 2005.
When Pfizer suspended sales of the drug in April 2005, Health Canada, the equivalent of the FDA, issued a stop-sale order which ensured that Bextra would not return to the market in Canada without approval from the public health agency.
Health Canada has since studied all of the available evidence on COX-2 inhibitors in general and Bextra specifically, and decided that "the manufacturer will not be able to bring Bextra back onto the Canadian market under its present conditions of use."
"The decision to stop the sale of Bextra," the agency said, "is based on information submitted by the manufacturer, Pfizer Canada Inc., and consultations with external experts and the public."
In the US, on February 12, 2006, the Chicago Tribune reported that "advisers to the Food and Drug Administration said Bextra should stay off the market permanently."
However, the task remains for Pfizer, to explain why, in light of the evidence now known to the public, did it allow Bextra to remain on the market until April 7, 2005.