Rofecoxib (IPA: [rofəˈ kɒksɪb]) is a nonsteroidal
anti-inflammatory drug (NSAID) developed by Merck & Co. to treat
osteoarthritis, acute pain conditions, and dysmenorrhoea. Rofecoxib was
approved as safe and effective by the Food and Drug Administration
on May 20, 1999 and was subsequently marketed under the brand name
Ceoxx and Ceeoxx.
Rofecoxib gained widespread acceptance among physicians treating
with arthritis and other conditions causing chronic or acute pain.
Worldwide, over 80 million people were prescribed rofecoxib at some
On September 30, 2004, Merck voluntarily withdrew rofecoxib from the
market because of concerns about increased risk of heart attack and
associated with long-term, high-dosage use. Rofecoxib was one of the
widely used drugs ever to be withdrawn from the market. In the year
withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.
Rofecoxib was available on prescription as tablets and as an oral
***How did Vioxx debacle happen?
By Rita Rubin, USA TODAY (October 10, 2004)
As drugmakers scramble to grab Vioxx's multi-billion-dollar share of
arthritis and pain-relief market, patients might find themselves
whether the competing medications are much safer.
The fact that no one can answer that question conclusively, and the
that Vioxx remained on the market as long as it did, point to serious
deficiencies in how the Food and Drug Administration regulates
prescription drugs, critics say.
Merck yanked Vioxx on Sept. 30 because a new study had found a higher
of heart attacks and strokes in patients taking the drug than in those
a placebo. The move was a stunning denouement for a blockbuster drug
had been marketed in more than 80 countries with worldwide sales
$2.5 billion in 2003. Vioxx, hawked by the likes of Olympic gold
Dorothy Hamill and Bruce Jenner, had been sold in the USA for more than
But the new Vioxx study was not the first to raise concerns about heart
attack and stroke risk. "We have been concerned and aware of the
for cardiovascular effects for the last few years," Steven Galson,
director of the FDA's Center for Drug Evaluation and Research, said the
day Merck announced the withdrawal. "This is not a total surprise."
In fact, in April 2000 the FDA required Merck to add labeling
about a possible link to such problems. Yet 2 million Americans were
taking Vioxx when it was pulled.
Critics describe the rise and fall of Vioxx as a cautionary tale of
masterful public relations, aggressive marketing and ineffective
regulation. "The FDA didn't do anything," says Eric Topol, chief of
cardiovascular medicine at the Cleveland Clinic. "They were passive
Sen. Chuck Grassley, R-Iowa, says the FDA was worse than passive.
Investigators for the Senate Finance Committee, which Grassley chairs,
Thursday with FDA researcher David Graham, lead scientist on a study
presented in August at a medical meeting in France.
May 1999: FDA approves Vioxx.
March 2000: Merck reveals that a new study found Vioxx patients had
the rate of serious cardiovascular problems than those on naproxen, an
older nonsteroidal anti-inflammatory drug, or NSAID.
November 2000: The New England Journal of Medicine publishes the
February 2001: An advisory panel recommends the FDA require a label
warning of the possible link to cardiovascular problems.
September 2001: The FDA warns Merck to stop misleading doctors about
Vioxx's effect on the cardiovascular system.
April 2002: The FDA tells Merck to add information about cardiovascular
risk to Vioxx's label.
Aug. 25, 2004: An FDA researcher presents results of a database
of 1.4 million patients; it concludes that Vioxx users are more likely
suffer a heart attack or sudden cardiac death than those taking
or an older NSAID.
Sept. 23, 2004: Merck says it learned this day that patients taking
in a study were twice as likely to suffer a heart attack or stroke as
those on placebo.
Sept. 30, 2004: Merck withdraws Vioxx from the U.S. and the more than
other countries in which it was marketed.
The study, an analysis of a database of 1.4 million Kaiser Permanente
members, found that those who took Vioxx were more likely to suffer a
heart attack or sudden cardiac death than those who took Celebrex,
main rival. Based on their findings, Graham and his collaborators
Vioxx to more than 27,000 heart attacks or sudden cardiac deaths
nationwide from the time it came on the market in 1999 through 2003.
Graham told the finance committee investigators that the FDA was trying
block publication of his findings, Grassley said in a statement. "Dr.
Graham described an environment where he was 'ostracized,' 'subjected
veiled threats' and 'intimidation,' " Grassley said. Graham gave
copies of e-mail that appear to support his claims that his superiors
suggested watering down his conclusions.
Rep. Tom Davis, R-Va., chair of the House Government Reform Committee,
last week wrote acting FDA commissioner Lester Crawford to ask what the
agency knew about Vioxx and when. Davis also asked whether the FDA
to collect more data on related drugs.
"In light of Merck's withdrawal of Vioxx ... and other recent news
examining FDA's review of the safety and efficacy of antidepressant
use by children, I am concerned whether FDA has been sufficiently
aggressive in monitoring drug safety," Davis wrote.
Topol, in a column posted last week on The New England Journal of
Medicine's Web site, called for a congressional review of the Vioxx
"catastrophe." "The senior executives at Merck and the leadership at
FDA share responsibility for not having taken appropriate action and
recognizing that they are accountable for the public health."
So far, Vioxx is the only drug in its class linked to a significant
increase in heart attacks and strokes. But the European Agency for the
Evaluation of Medicinal Products last week announced it will review all
long-term cardiovascular safety data for Vioxx and the four other
drugs licensed in Europe.
"It is important to note that the results of clinical studies with one
drug in a given class are not necessarily applicable to others in a
class," Peter Kim, president of Merck Research Laboratories, was quick
say at a news conference announcing Vioxx's withdrawal.
Merck happens to have a Vioxx classmate called Arcoxia in the wings. It
sold in 47 countries but not yet in the USA. The company expects to
about its application to the FDA by month's end, spokesman Christopher
Like ibuprofen and naproxen, Vioxx is a non-steroidal anti-inflammatory
drug, or NSAID. But Vioxx belongs to a fairly new class of NSAIDs
COX-2 inhibitors. With Vioxx's demise, Pfizer's Celebrex and Bextra are
the only COX-2 inhibitors sold in U.S. markets.
No one has ever said that COX-2 inhibitors are more effective than
NSAIDs. Their selling point always has been that they're less likely
cause bleeding and other digestive tract complications.
Although FDA approved the COX-2 inhibitors, it wasn't convinced they
safer. The drugs had to carry the same digestive warning as classic
NSAIDs. So Merck and Pharmacia, which later merged with Pfizer,
studies to prove their drugs shouldn't be lumped with other NSAIDs.
The Celebrex trial failed to convince the FDA that the drug was safer,
it didn't appear to be riskier, either. Merck's trial backfired. Though
the study did demonstrate that Vioxx was safer on the digestive tract
naproxen, it also unexpectedly found that the COX-2 inhibitor doubled
risk of cardiovascular problems.
In a written response to Topol's New England Journal of Medicine
Merck said it "promptly disclosed these results to the FDA, the
community and the media beginning in March 2000."
But from the start, Merck put a positive spin on the data. A press
on March 27, 2000, led off with the finding that Vioxx caused fewer
digestive tract problems than naproxen. It did go on to say that
"significantly fewer thromboembolic events (in other words, heart
and strokes) were observed in patients taking naproxen."
However, it wasn't that Vioxx caused cardiovascular problems, but that
naproxen protected against them, Merck argued for the next 4½ years.
Merck acknowledged in the March 2000 press release, "this effect ...
not been observed previously in any clinical studies for naproxen."
In February 2001, Merck tried to convince an FDA advisory committee
Vioxx be allowed to drop the digestive tract warning. But the committee
couldn't ignore the cardiovascular findings.
Still, Merck's marketing machine churned on. In September 2001, the FDA
ordered the company to send doctors a letter "to correct false or
misleading impressions and information" about Vioxx's effect on the
In April 2002, the FDA followed its advisory panel's recommendation and
required that Merck note a possible link to heart attacks and strokes
"Meanwhile," Topol writes in The New England Journal of Medicine,
was spending more than $100 million a year in direct-to-consumer
advertising - another activity regulated by the FDA and a critical
mechanism in building the 'blockbuster' status of a drug."
Direct-to-consumer advertising was meant to heighten awareness of
not to hype them, says pharmacologist Raymond Woosley, vice president
health sciences at the University of Arizona. "Do we need to be told
much greater one drug is than the other?" Woosley asks. "The public
understand the subtle differences."
Merck continued to minimize unfavorable findings up to a month before
withdrawing Vioxx. On Aug. 26, the company fired off a press release
refuting Graham's study. "Merck stands behind the efficacy, overall
safety and cardiovascular safety of Vioxx," it said.
Only randomized, controlled trials, in which patients are randomly
assigned to treatment groups (the type of study that first raised heart
concerns back in 2000) can provide unimpeachable data about a drug's
safety and effectiveness, the release pointed out.
Finally, late last month, Merck confronted unfavorable findings that it
could not explain away. Merck had sponsored a three-year, 2,600-patient
randomized trial to see whether Vioxx, like Celebrex, could claim that
protects against the recurrence of colon polyps, which can become
Again, the study backfired. After 18 months of treatment, researchers
observed a higher heart attack and stroke risk in patients on Vioxx,
says. The drug was compared with a placebo and not another NSAID, so
could not divert blame away from Vioxx. Merck has not yet reported the
study results, but the FDA says 3.5% of the subjects on Vioxx had
a heart attack or stroke, compared with 1.9% on placebo.
***Monitoring the drugs
FDA spokeswoman Crystal Rice says the agency will continue to monitor
drugs in the same class as Vioxx. Besides Merck's Arcoxia, the FDA is
considering whether to approve Novartis' Prexige. Pfizer is expected to
resubmit an application for parecoxib by year's end. The FDA turned
its original application in 2001 for lack of data.
Since becoming aware of the Vioxx study's finding, Rice says, the FDA
"much more sensitized to the possibility of seeing this adverse event"
Simply looking for heart attacks and strokes in individuals taking the
drugs isn't enough, says Alastair Wood, chair of pharmacology at
Sometimes, a drug triggers such an unusual problem that it's fairly
to connect the dots, Wood says. "But there was no possibility that you
could discern a heart attack due to Vioxx from a heart attack not due
Vioxx," he says.
Wood, Topol and others speculate that drugs in the same class as Vioxx
appear to be safe because the FDA has not yet asked for the randomized,
controlled trials necessary for definitive answers.
"The spotlight is now on Pfizer and the FDA," says Garret FitzGerald,
chair of pharmacology at the University of Pennsylvania. "The agency
to scrutinize all ongoing trials in the light of these data and to
swiftly" if all COX-2 inhibitors should carry a warning about heart
attacks and strokes.
Topol says the drugs should be specifically tested in patients known to
have cardiovascular disease, which is common in patients who need
medication for osteoarthritis. So far, such patients have virtually
excluded from trials of the COX-2 inhibitors, Topol says.
In a yearlong study of more than 18,000 osteoarthritis patients
in August, Prexige did not increase heart attack or stroke risk when
compared with ibuprofen or naproxen. However, Topol wrote in an
accompanying editorial, fewer than 2% of study participants had had a
heart attack or undergone bypass surgery or angioplasty before
Back in 2000, when Merck first notified the FDA that Vioxx appeared to
carry a higher risk of heart attacks and strokes than naproxen, the
should have quickly ordered a trial comparing Vioxx with a placebo,
says. In the end, he notes, "a relatively small study was all that it
to show this problem."
***Meanwhile, patients try not to worry.
Marjorie Chepp of Milwaukee had been taking Vioxx for nearly two years.
Her doctor first prescribed it for a knee injury, but Chepp found that
also relieved her osteoarthritis and fibromyalgia. She asked to remain
"For years I had refused to take meds other than over-the-counter
I was always afraid of the long-term effects," says Chepp, 47, an
instructor who had an ulcer at 16. "Of course, what happens with the
one I take? It gets recalled."
***Diabetes drug Rezulin taken off market
CNN News (March 23, 2000)
Pill linked to 63 liver-poisoning deaths
WASHINGTON (CNN) -- Rezulin
once-hailed diabetes drug used by about 750,000 Americans, has been
withdrawn from the market after it was linked to at least 63 deaths
The U.S. Food and Drug Administration, which requested the action
Tuesday, urged Rezulin patients not to stop taking the drug without
contacting their doctors.
It said two newer drugs -- Avandia and Actos -- offer the same benefits
Rezulin with less risk.
While Rezulin's manufacturer agreed to remove it, a statement from
Parke-Davis/Warner-Lambert indicated the company still had confidence
the drug, which was prescribed for Type 2 -- or adult onset -- diabetes
patients who had not responded to other therapies.
In its statement, the drug-maker said it still thought the benefits of
Rezulin (known generically as troglitazone) outweighed its risks but
decided it "is in the best interest of patients to discontinue
Rezulin at this time."
"Repeated media reports sensationalizing the risks associated with
therapy have created an environment in which patients and
physicians are simply unable to make well-informed decisions regarding
safety and efficacy of Rezulin," the statement said.
***'Unacceptably high risk'
The FDA acted after mounting pressure from the Public Citizen Health
Research Group, a consumer-advocacy organization, and even from some
In one case, FDA medical officer Dr. Robert Misbin, one of Rezulin's
reviewers within the agency, asked some members of Congress to
investigate why his bosses had not pulled the pill from the market.
"I am writing to enlist your aid in convincing my superiors at FDA that
Rezulin should be removed from the market because of its unacceptably
risk of causing liver failure," Misbin wrote earlier this month.
"Patients should not discontinue taking Rezulin or other treatments for
diabetes without discussing alternative therapies with their
Until recently, FDA managers had insisted Rezulin benefited numerous
diabetics whose disease isn't helped by any other drugs.
Dr. Sidney Wolfe, who heads Public Citizen and is a frequent critic of
FDA, said the drug should have been withdrawn long ago. He described
Rezulin -- which went on the market in March 1997 -- as "one of the
dangerous drugs" on the market.
Glaxo Wellcome, which sold Rezulin in Britain, suspended sales of the
there in December 1997.
Public Citizen first petitioned the FDA in July 1998 to remove Rezulin.
"Easily more people have died between the time of our petition and when
this belated ... (FDA) ... action was taken," Wolfe said.
***FDA: Other drugs 'offer same benefits'
According to the FDA announcement, a review of recent safety data
that Rezulin was more toxic to the liver than the two newer drugs.
to date show that Avandia and Actos, both approved in the past year,
the same benefits as Rezulin without the same risk," the FDA said.
Rosa Delia Valenzuela, left, died in Los Angeles in 1998 from liver
failure after taking Rezulin.
"We are now confident that patients have safer alternatives in this
important class of diabetes drugs," said Dr. Janet Woodcock, director
the FDA's Center for Drug Evaluation and Research.
But Woodcock also stressed that although Actos and Avandia appeared
on the liver than Rezulin, the agency is still watching for any serious
side effects from either product.
"We are not saying we are confident these drugs will not cause liver
toxicity," Woodcock said. "What we are saying is we believe they are
safer" than Rezulin.
***Deaths linked to Rezulin
Rezulin was well-received when it went on the market because it was the
only drug available that restored the body's sensitivity to insulin.
But since its introduction, Rezulin has been linked to 90 cases of
failure. Of that total:
* 63 people died (including three who underwent liver transplants)
* 7 people who had a liver transplant survived
* 10 people recovered without a transplant
* 10 people are still suffering from liver failure
After the FDA began receiving reports of Rezulin patients suffering
liver failure, it ordered the manufacturer to put stronger
liver-toxicity warnings on the drug . An FDA advisory committee also
recommended that the drug be available to only a select group of
patients -- those whose diabetes was not well-controlled by other