Yourlawyer.com (Celebrex Lawsuit News)

Baystate Medical Center Subpoenaed Over Fake Drug Studies

Wed, 08 Apr 2009 00:00:00 -0700

The Baystate Medical Center has received a subpoena as part of a federal investigation into a doctor there who falsified 21 drug studies. According to The Wall Street Journal, the U.S. Attorneys office in Boston is seeking financial records related to the work of Dr. Scott S. Reuben.

As we reported last month, medical journals have been asked to retract studies involving Vioxx, Celebrex, Lyrica and other drugs. All of the studies were published between 1996 and 2008. According to The Wall Street Journal, the journal Anesthesia & Analgesia has retracted 10 studies. It also posted a list of 11 others that were published in other journals on its Web site. The journal Anesthesiology said it has retracted three of Reuben’s articles.

These studies had a great deal of influence on the practice of medicine. Because of Reuben’s “research”, it had become routine for doctors to combine the use of painkillers like Celebrex and Lyrica for patients undergoing common procedures such as knee and hip replacements. Reuben even had the ear of the Food & Drug Administration, and had written the agency asking it not to restrict the use of many of the painkillers he studied. He often cited his fake data to make his case, the Journal said.

Many of the studies Reuben worked on involved drugs that have very serious side effects. Like many antidepressants, the labeling of Effexor warns that it has been linked to suicides in young people and children. Both Celebrex and Vioxx have been linked to heart attacks and strokes, and Vioxx was actually recalled in 2006 because of these problems.

Not surprisingly, Reuben has strong ties with the pharmaceutical industry. According to the Journal, he had been a paid speaker on behalf of Pfizer - the maker of Lyrica and Celebrex - and it paid for some of his research. Wyeth provided $10,000 in grant money to. Reuben from 2001 to 2003, the Journal said. Merck also funded some of Reuben's work.

According to The Wall Street Journal, Baystate Medical is cooperating fully with the federal government's probe of Reuben. A spokesperson for the Springfield, Mass., medical center told the Journal that Baystate isn't a target of the investigation.

Baystate Medical Center has placed Reuben on indefinite leave. He has also vacated an appointment as a professor at Tufts University’s medical school, the Journal said.

Researcher Faked Data for 21 Studies Involving Vioxx, Celebrex and Other Drugs

Wed, 11 Mar 2009 00:00:00 -0700

Medical journals have been asked to retract 21 studies that touted the benefits of Vioxx, Celebrex and other drugs. According to The Wall Street Journal, Baystate Medical Center, Springfield, Mass. is asking the journals to make the retractions because its former chief of acute pain, Dr. Scott S. Reuben, had faked data used in the studies.

In addition to Vioxx and Celebrex, some of the 21 studies involved the fibromyalgia drug Lyrica and the antidepressant Effexor XR. Reuben's study claimed to show that these drug worked well as painkillers, the Journal said. All of the studies were published between 1996 and 2008.

According to The Wall Street Journal, these studies had a great deal of influence on the practice of medicine. Because of Reuben's "research", it had become routine for doctors to combine the use of painkillers like Celebrex and Lyrica for patients undergoing common procedures such as knee and hip replacements, the Journal said.

Reuben even had the ear of the Food & Drug Administration (FDA), and had written the agency asking it not to restrict the use of many of the painkillers he studied. He often cited his fake data to make his case, the Journal said.

According to The Wall Street Journal, Reuben's fraud has caused the journal Anesthesia & Analgesia to retract 10 studies. It also posted a list of 11 others that were published in other journals on its Web site. The journal Anesthesiology said it has retracted three of Reuben's articles.

Not surprisingly, Reuben has strong ties with the pharmaceutical industry. According to the Journal, he had been a paid speaker on behalf of Pfizer - the maker of Lyrica and Celebrex - and it paid for some of his research.

Baystate Medical Center has placed Reuben on indefinite leave. He has also vacated an appointment as a professor at Tufts University's medical school, the Journal said.

Perhaps the most disturbing aspect of this scandal is that many of the drugs Reuben researched have been linked to serious side effects. Like many antidepressants, the labeling of Effexor warns that it has been linked to suicides in young people and children.

Both Celebrex and Vioxx have been linked to heart attacks and strokes, and Vioxx was actually recalled in 2006 because of these problems.

This is actually not the first time the integrity of studies involving Vioxx have come into question. Last April, we reported that an analysis of court documents uncovered in the course of Vioxx injury lawsuits found that Merck & Co. employees worked alone or with publishing companies to write Vioxx study manuscripts and later recruited academic medical experts to put their names as first authors on the studies. According to the analysis, which was published in the Journal of the American Medical Association, Merck’s involvement in producing the data wasn’t disclosed in many cases.

Vioxx, Celebrex, Other Painkillers Up Risks for Heart Failure, Heart Attack Patients

Wed, 12 Nov 2008 00:00:00 -0800

Vioxx, Celebrex, ibuprofen and other NSAID painkillers increase the chances that heart attack and heart failure patients will experience a second heart attack or death, a new study says. According to Danish researchers, the risk of a second heart attack or death actually doubled within the first 90 days of starting Vioxx or Celebrex. Other painkillers, like ibuprofen, increased the risk between 2.1 and 1.3 times.

The study was presented this week at the American Heart Association meeting in New Orleans. At least one of the researchers recommended that physicians now avoid these types of painkillers, or use low doses, in patients with a history of heart attack or heart failure.

For their study, researchers at the University of Copenhagen analyzed the records of 58,432 patients who had a previous heart attack and 107,092 with heart failure in Denmark. Of those, 36 percent of the heart attack patients and 34 percent of the heart failure patients said they took at least one painkiller after they were discharged from the hospital.

Patients who had suffered a heart attack and were taking the painkiller Vioxx had 2.7 times the risk of having another heart attack or dying compared with patients not taking painkillers. Heart attack patients taking Celebrex had double the risk, while those with heart failure taking Celebrex had 2.3 times the risk. Heart attack patients taking diclofenac had 1.9 times the risk, while those taking ibuprofen had 1.3 times the risk, according to the study.

NSAIDs are the most prescribed medications for treating conditions such as arthritis. The Food & Drug Administration (FDA) now requires all NSAIDs to bear a black box warning regarding heart attack and stroke risks. The warnings were added to the drugs after Vioxx was recalled in 2004.

The FDA ordered Vioxx off the market in 2004 after studies showed that people who took the drug had a higher risk for heart attack. The recall came after an analysis of patients using Vioxx linked the defective drug to more than 27,000 heart attacks or sudden cardiac deaths in the U.S. from 1999 through 2003. Since then, Vioxx the subject of thousands of drug injury law suits.

COX-2 Inhibitors More Likely to Raise Heart Risks Than Other NSAIDs

Wed, 05 Nov 2008 00:00:00 -0800

A new study that confirms the heart risks associated with a class of drugs called NSAIDs has found that the increased risk correlates to the specific pain-causing molecule they act against. According to the study, NSAIDS that are cox-2 inhibitors are more likely to increase the risks of heart attacks and strokes.

NSAIDs are the most prescribed medications for treating conditions such as arthritis. Most people are familiar with over-the-counter, nonprescription NSAIDs, such as aspirin and ibuprofen. NSAIDs also include prescription drugs like Celebrex, as well as the now-banned Vioxx.

NSAIDS target different forms of cyclooxygenase, an enzyme whose activity increases inflammation and pain. Older NSAIDs, such as ibuprofen and naproxen, act primarily against cox-1. Celebrex, Vioxx and Bextra act against cox-2. While cox-2 inhibitors reduce the gastrointestinal bleeding, pain and inflammation that are major side effects of the cox-1 drugs, they have been found to increase the risk of heart attack and stroke.

This latest study, conducted by researchers in Spain and Italy, looked at 8,852 people who had heart attacks. The increase was related to both the dosage and the length of time the drugs were taken. But the risk was increased by 18 percent by NSAIDS that acted against cox-1, compared to a 60 percent increase for those with the greatest cox-2 activity.

"We found a significant correlation between the degree of inhibition in vitro [in the laboratory] of whole blood cox-2, but not whole blood cox-1," said the report by researchers in Spain and Italy.

The Food & Drug Administration (FDA) now requires all COX-2 inhibitors and NSAIDs to bear a black box warning regarding heart attack and stroke risks. The warnings were added to the drugs after Vioxx was recalled in 2004.

Vioxx was approved for use in 1999, and quickly became a blockbuster for Merck, with annual sales of $2.5 billion. But the FDA ordered Vioxx off the market in 2004 after studies showed that people who took the drug had a higher risk for heart attack. The recall came after an analysis of patients using Vioxx linked the defective drug to more than 27,000 heart attacks or sudden cardiac deaths in the U.S. from 1999 through 2003. Since then, Vioxx the subject of thousands of drug injury law suits.

Late last year, Merck announced that it would a $4.85 billion settlement with Vioxx plaintiffs. Under the terms of the Vioxx settlement, Merck set up $4 billion fund for people who claim they suffered heart attacks as a result of Vioxx, and another $850 million fund for those who suffered ischemic strokes. Initial payments for the Vioxx settlement started going out to some plaintiffs last month.

Pfizer Announces Bextra, Celebrex Settlement

Fri, 17 Oct 2008 00:00:00 -0700

Pfizer has reached a tentative agreement to settle lawsuits involving its Bextra and Celebrex painkillers for $894 million. If it goes forward, the Pfizer Bextra and Celebrex settlement will resolve roughly 90 percent of the personal injury lawsuits the company faces because of the drugs.

Celebrex and Bextra are COX-2 inhibitors, a class of drugs that also includes Merck’s recalled Vioxx. Such medications are linked to an increased risk of blood clots, heart attacks and strokes. Pfizer withdrew Bextra from the market in 2005, and Celebrex is the only COX-2 inhibitor still on the market in the United States.

Celebrex carries the Food and Drug Administration’s (FDA) strictest “black-box” warning on its drug label, stating that it may cause an increased risk of serious cardiovascular events such as heart attacks and strokes. Despite its apparent risk, Celebrex continued to generate $2.3 billion in sales in 2007, a 12 percent increase from the previous year.

According to The New York Times, $760 million of the Bextra and Celebrex settlement would go to settle roughly 7,000 personal injury cases, $60 million will cover settlements with attorneys general in the 33 states and the District of Columbia, and $89 million will cover consumer fraud class action cases over reimbursement for money spent on the two drugs.

Pfizer said it hopes to finalize the settlement by the end of the year. A spokesperson for the company said that Pfizer would also like to include many of the remaining personal injury lawsuits the settlement. The company will fight those not settled with court motions or at trial.

COX-2 inhibitors have been the subject of safety worries since 2004, when Merck pulled Vioxx from the market. The FDA ordered the painkiller off the market after an analysis of patients using Vioxx linked the defective drug to more than 27,000 heart attacks or sudden cardiac deaths in the U.S. from 1999 through 2003. The Vioxx recall led to thousands of lawsuits.

Last November, Merck announced a $4.85 billion settlement with the thousands of people who had filed Vioxx injury lawsuits. Under the terms of the settlement, Merck set up a $4 billion fund for people who claim they suffered heart attacks as a result of Vioxx, and another $850 million fund for those who suffered ischemic strokes. Partial settlement payments started going out to some Vioxx plaintiffs last month.

Ketek, Avandia Among Drugs Doctors Won't Take

Mon, 23 Jun 2008 00:00:00 -0700

When doctors were recently asked which commonly prescribed medications they would avoid, they came up with the following eight. Perhaps you might want to reconsider these medications as well. At a minimum, speak to your doctor, as there are safer options for all of these medications.

Advair: This asthma medication contains the long-acting beta-agonist (LABA) salmeterol. A 2006 study of 19 trials, which was published in the Annals of Internal Medicine, revealed that with regular use, LABAs can increase asthma attack severity. Salmeterol is more widely prescribed than other LABAs, thus the danger is greater and may contribute to as many as 5,000 asthma-related deaths in the United States annually. Another study that same year led the US Food and Drug Administration (FDA) to label Advair with a "black box,” the FDA’s strongest warning.
Avandia: In September, the Journal of the American Medical Association (JAMA) revealed in a study that those taking diabetes drug Avandia—or rosiglitazone—for at least one year suffered an increased risk of heart failure (109 percent) or a heart attack (42 percent). One possible reason is that Avandia may cause dangerous fluid retention or raise artery-clogging LDL cholesterol. The FDA asked Avandia maker, GlaxoSmithKline, to conduct a long-term study assessing users' heart risks; however, that study is not expected to commence until later this year.
Celebrex: This pain medication is linked to increased risks of stomach bleeding, kidney trouble, and liver damage. According to a 2005 New England Journal of Medicine study people taking 200 mg of Celebrex twice daily more than doubled their risk of dying of cardiovascular disease; those on 400 mg twice daily more than tripled their risk. By the way, two other drugs in this drug class—Bextra and Vioxx--were banned for similar heart damage risks, yet Celebrex remains available.
Ketek: This antibiotic, generally prescribed for respiratory-tract infections, carries a higher risk of severe liver side effects, has been linked to heart-rhythm problems and liver disease, and can interact with other medications. Although still prescribed, the FDA limited Ketek’s usage to the treatment of pneumonia early last year.
Prilosec and Nexium: The FDA has investigated a suspected link between cardiac trouble and acid-reflux drugs Prilosec and Nexium. Also, because both drugs are proton-pump inhibitors, they may be overly effective at stopping stomach acid production, raising pneumonia, bone loss risk, and fracture risk (this, by over 40 percent in patients on long-term use).
Original Visine: Because Visine shrinks ocular blood vessels in the same way Afrin does nasally, overuse of its active ingredient tetrahydrozoline can create an endless loop of vessel dilating-and-constricting that may cause more redness, increasing the need for more Visine, causing more redness, and so on.
Pseudoephedrine: Other than that this decongestant is a critical component in methamphetamine, it can raise blood pressure and heart rate, has been linked to heart attacks and strokes, and can increase symptoms of benign prostate disease and glaucoma.

Pfizer Negotiating Celebrex, Bextra Settlements

Mon, 05 May 2008 00:00:00 -0700

Celebrex and Bextra maker Pfizer Inc. has begun to settle injury claims against the painkillers. It is estimated that between 7,000 and 9,000 Celebrex and Bextra cases have been filed by people who claim the defective painkillers caused heart attacks and strokes. According to a report in Friday's Wall Street Journal, lawyers representing Pfizer have indicated the company is willing to pay as much as $500 million to resolve all outstanding cases.

Celebrex and Bextra are COX-2 inhibitors, a class of drugs that also includes Merck's recalled Vioxx. Such medications are linked to an increased risk of blood clots, heart attacks and strokes. Pfizer withdrew Bextra from the market in 2005, and Celebrex is the only COX-2 inhibitor still on the market in the United States.

According to The Wall Street Journal, Pfizer has reached settlements with three law firms representing more than 200 of the thousands who sued over the drugs. Firms have been offered $40,000 to $50,000 a client to resolve Celebrex cases and as much as $200,000 a client for Bextra. The Wall Street Journal reported that unlike Merck's recent mass settlement of litigation involving Vioxx, Pfizer is attempting to resolve its Bextra and Celebrex lawsuits on a firm-by-firm basis.

Celebrex carries the Food and Drug Administration’s strictest “black-box” warning on its drug label, stating that it may cause an increased risk of serious cardiovascular events such as heart attacks and strokes. Despite its apparent risk, Celebrex continued to generate $2.3 billion in sales in 2007, a 12 percent increase from the previous year.

Last month, the National Cancer Institute released an analysis of six Celebrex studies that included 7,950 patients. According to The Wall Street Journal, the analysis showed Celebrex was associated with an increased risk of cardiovascular death, heart attack, stroke, heart failure or thromboembolic event, or events related to blood clots, compared to patients not taking the drug. The researchers found that patients receiving the highest dose of Celebrex of 400 milligrams twice daily had a nearly three times higher risk of heart attacks and strokes than patients not taking the drug. Patients taking a lower dose of Celebrex, 400 milligrams once daily, had a 10% higher risk of a cardiovascular event. The study did not look at patients taking a once-daily, 200-milligram dose of Celebrex, which represents the way the drug is most commonly prescribed.

The first Bextra trial was due to begin today in federal court in San Francisco. But a lawyer involved in the case told The Wall Street Journal that the parties agreed to adjourn the case so Pfizer could attempt to settle Celebrex and Bextra cases across the country.

Celebrex in High Doses Linked to Higher Stroke, Heart Attack Risks

Tue, 01 Apr 2008 00:00:00 -0700

Higher doses of Celebrex are a risky choice for patients with heart problems, a new study suggests. The results of this latest Celebrex study, supported by the National Cancer Institute, indicate that doctors should use caution in prescribing the prescription pain reliever, and should use low doses when they use Celebrex to treat people at a high risk for heart problems.

Celebrex belongs to a class of drugs known as COX-2 inhibitors and is the only such drug still on the market in the US. Blocking the COX-2 enzyme impedes the production of the chemical messengers (prostaglandins) that cause the pain and swelling of arthritis inflammation. COX-2 inhibitors have been linked to an increased risk of blood clots, heart attacks and strokes. In 2004, another COX-2 inhibitor, Vioxx was removed from the market after studies linked it to more than 27,000 heart attacks or sudden cardiac deaths in the U.S. from 1999 through 2003. Another COX-2 inhibitor called Bextra was also pulled from the US market due to safety concerns.

Celebrex carries the Food and Drug Administration's strictest "black-box" warning on its drug label, stating that it may cause an increased risk of serious cardiovascular events such as heart attacks and strokes.

The National Cancer Institute's Celebrex study consisted of a combined analysis of six studies of the Pfizer pain drug, and included 7,950 patients. According to The Wall Street Journal, the analysis showed Celebrex was associated with an increased risk of cardiovascular death, heart attack, stroke, heart failure or thromboembolic event, or events related to blood clots, compared to patients not taking the drug. The risk was not affected by aspirin use.

The researchers found that patients receiving the highest dose of Celebrex of 400 milligrams twice daily had a nearly three times higher risk of heart attacks and strokes than patients not taking the drug. Patients taking a lower dose of Celebrex, 400 milligrams once daily, had a 10% higher risk of a cardiovascular event.

The study did not look at patients taking a once-daily, 200-milligram dose of Celebrex, which represents the way the drug is most commonly prescribed. Dr. Steven Nissen of the Cleveland Clinic, who has a study on lower doses underway, told Reuters that the conclusions that could be based on this latest Celebrex study were limited. "There aren't long-term randomized placebo-controlled trials for that dose, The only way we're ever going to answer these questions is with good randomized prospective data," he said. "We'll tell it like it is when the data is in."

Ex Pfizer Sales Manager Indicted For Allegedly Obstructing Off-label Marketing Probe

Fri, 14 Mar 2008 00:00:00 -0700

An investigation of Pfizer Inc. drug marketing efforts has resulted in charges being filed against a former Pfizer sales manager. The four count indictment alleges that the former Pfizer employee tried to obstruct an investigation into possible off-label marketing of some Pfizer medications.

The four-count indictment issued by the U.S. District Court in Massachusetts stemmed from an investigation into charges that Pfizer was marketing two drugs for unapproved uses. Though doctors are allowed to prescribe approved drugs any way they see fit, drug companies are barred from promoting such off-label uses.

Though the indictment does not name which Pfizer drugs were the subject of the investigation, the Pharmalot Website is reporting they were Bextra and Celebrex.

Celebrex and Bextra are COX-2 inhibitors, a class of drugs linked to an increased risk of blood clots, heart attacks and strokes. Pfizer withdrew Bextra from the market in 2005, and Celebrex is the only COX-2 inhibitor still on the market in the United States.

Thomas Farina, 41, of Fairport, N.Y., supervised about 10 Pfizer sales representatives in the Brooklyn, N.Y., area. According to the indictment, Farina is accused of altering and deleting computer files, as well as instructing employees he supervised to do the same, despite knowing that Pfizer was under investigation for promoting two drugs for unapproved uses. The indictment said Farina had been given specific instructions to preserve all documents related to the investigation.

The indictment alleges that Farina changed the clock on his computer and then altered and re-saved files to make them appear to have been changed at an earlier time. Many of the files, which involved instructions to promote drugs at unapproved dosages or for unapproved uses, were then deleted, according to the indictment.

The indictment also alleges that Farina told others to alter and delete documents related to the investigation of off-label drug promotions. The investigation found that Farina had known that Pfizer was being probed for off-label marketing at the time he deleted the files.

If convicted, Farina would face up to 20 years in jail and a $250,000 fine on each of the four counts against him.

Celebrex, other COX-2 Inhibitors May Cause Heart Arrhythmias

Thu, 17 Jan 2008 00:00:00 -0800

Research on fruit flies and rats has found that COX-2 inhibitors, a class of painkillers that includes Celecoxib (brand name Celebrex) and the ill-fated Vioxx, can cause heart arrhythmias. Since Vioxx was pulled from the market several years ago after being linked to heart attacks, research on COX-2 inhbitors has become more vigrourous.

In both fruit fly and rat models, researchers discovered that Celebrex can induce heart arrhythmia. More interestingly, this effect is independent of the COX-2 enzyme. Arrhythmias are disorders of the regular rhythmic beating of the heart and can occur in a healthy heart and be of minimal consequence. They may also indicate a serious problem and lead to heart disease, stroke, or sudden cardiac death. COX-2 inhibitors are newly developed drugs for inflammation that selectively block the COX-2 enzyme. Blocking the COX-2 enzyme stops the production of the chemical messengers—or prostaglandins—that cause the pain and swelling of arthritis inflammation. COX-2 selective inhibitors are a new class of nonsteroidal anti-inflammatory drugs, or NSAIDs that directly targets the COX-2 enzyme. Because they selectively block the COX-2 enzyme—the enzyme responsible for inflammation and pain—and not the COX-1 enzyme, these drugs are uniquely different from traditional NSAIDs.

Satpal Singh and colleagues tested various Celecoxib doses on the heart rate of Drosophila, a genus of small flies often referred to as fruit flies or vinegar flies, because of their tendency to linger around over-ripe or rotting fruit, and a good model for human cardiac pharmacology. To their surprise, administering 3 ƒÝm Celecoxib—which is not much higher than the plasma levels in humans taking the drug—reduced the heart rate and increased beating irregularities, while 30 ƒÝm was enough to stop the heart within one minute. Researchers were surprised at the results because Drosophila do not have COX-2 enzymes. Rather, Celecoxib could directly inhibit the potassium channels that help generate the electric current that drives heartbeat. The researchers were able to achieve similar heart-stopping results in rat cardiac cells, whereas aspirin, another potent COX-2 inhibitor, had no effect, confirming that another mechanism is at work. The drug also inhibited rat and human potassium channels expressed in a human cell line.

Singh and colleagues point out that since these arrhythmia effects bypass COX-2, it is unclear if other COX-2 inhibitors would yield similar results. They also stress it is too early to speculate on human effects, although their results suggest Drosophila—one of the most valuable of organisms in biological research and has been used as a model research organism for almost a century—are a valuable tool to investigate other COX-2 drugs.

Late last summer, authors of an article published in a special cardiology issue of The Lancet wrote that use of celecoxib after stent implantation in patients with coronary artery disease is safe, reducing the need revascularisation of the target lesion; however, an accompanying comment warned that clinical trials indicated that long-term use of celecoxib can expose patients to an additional risk of heart attack.

A 2006 review of 138 randomized trials and almost 150,000 participants revealed selective COX-2 inhibitors were associated with a moderately increased risk of vascular events, mainly due to a twofold-increased risk of myocardial infarction.

Celebrex TV Advertisement Under Fire

Mon, 09 Apr 2007 00:00:00 -0700

Last week, Pfizer began airing its controversial two-and-a-half-minute commercial promoting the painkiller Celebrex, which is in the same class of drugs as the discredited (and discontinued) Vioxx. For Celebrex, a type of non-steroidal anti-inflammatory drug (NSAID) known as a COX-2 inhibitor, it was a return to television marketing for the first time in more than two years. However, Pfizer may now be forced to pull the ad in the face of mounting criticism that the spot is misleading.

Today, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, sent a letter to Andrew Von Eschenbach, commissioner of the U.S. Food and Drug Administration (FDA), to raise his concerns. Calling the ad “misleading” and “dangerous,” Wolfe wants the FDA to order Pfizer to immediately pull the commercial from the airwaves.

“The overall purpose of the ad is to make it appear, contrary to scientific evidence, that the cardiovascular dangers of Celebrex are not greater than those of any of the other NSAID painkillers,” Wolfe writes. “Further, it asserts that certain gastrointestinal problems are, if anything, less frequent with Celebrex than with two popular over-the-counter (OTC) painkillers.

“The ad violates FDA law and regulations because it contains several false or misleading statements that will lead many viewers to underestimate the cardiovascular and gastrointestinal risks of Celebrex and use it in preference to equally effective, safer alternatives such as OTC naproxen.”

Wolfe takes Pfizer to task specifically for three potentially false and misleading claims. The first controversial claim made in the spot points to the cardiovascular risks of Celebrex competitors like ibuprofen and naproxen. But as Wolfe states, “In a thorough review of all randomized controlled trials of older NSAIDs such as ibuprofen and naproxen, as well as the newer COX-2 NSAIDs such as Vioxx and Celebrex, published almost one year ago, the authors concluded that the COX-2 drugs, including Celebrex, did have an increased cardiovascular risk, seen most clearly with heart attacks (myocardial infarctions)….” He also notes that naproxen was not associated with increased cardiovascular risk in that review.

Secondly, Pfizer says in their ad that Celebrex has the same FDA-mandated cardiovascular warning as the other NSAID drugs. While this is true for prescription drugs, OTC NSAIDs such as naproxen and ibuprofen are not required to have the same black-box warning. According to the FDA, short-term use of low-dose OTC NSAIDs is not associated with any increased cardiovascular risk. Wolfe also points out that, according to the American Heart Association (AHA), “important differences exist between these agents in terms of risk of major thrombotic events.”

“Following the withdrawal of both Vioxx and Bextra,” Wolfe explains, “in each case involving increased cardiac risks of these COX-2 drugs, the FDA issued a statement requiring boxed warnings of increased cardiovascular risk on the prescription versions of all older (non-selective) NSAIDs and the remaining COX-2 drug, Celebrex. The FDA also explained, however, why the over-the-counter NSAIDs such as naproxen and ibuprofen would be available without such a boxed warning.”

The third point of contention in the ad relates to the issue of gastrointestinal damage and Pfizer’s claim that “a lower percentage of patients on Celebrex reported indigestion, abdominal pain, and nausea versus prescription ibuprofen and naproxen.” While it’s true that all NSAIDs carry a warning of stomach or intestinal problems, Wolfe says, this statement does not account for “more serious problems, ulcers or bleeding, [which] occur equally with all NSAIDs.”

Merck's Worst Nightmare, a Study that Shows Vioxx Heart Attack Risk Linked to (Very) Short-Term Use

Wed, 03 May 2006 00:00:00 -0700

Throughout the Vioxx saga, Merck has always taken refuge behind its assertion that short-term use of the COX-2 inhibitor cannot be linked to an increased risk of heart attack or stroke. Merck itself, however, acknowledges long-term use of the drug does carry such an increased risk. In fact, the long-term adverse implications of Vioxx use led to the voluntary withdrawal of the drug in September, 2004.

To a great extent, Merck has legitimized its strategy of refusing to settle any of the roughly 12,000 Vioxx personal injury and wrongful death cases on the basis of its conviction that it should ultimately prevail on all of the short-term cases (by dismissal, verdict, or on appeal) thereby eliminating about half of the cases.

Merck also believes that even many of the long-term-use Vioxx plaintiffs suffered their injuries (or deaths) as a result of one or more chronic medical condition such as cardiovascular disease, diabetes, hypertension, or obesity.

Thus, the pharmaceutical giant sees no reason to enter into a global settlement of all pending lawsuits against it as long as the company and its attorneys still perceive so many “defensible” cases exist.

Unfortunately for Merck, however, things have not turned out that way since it has already lost three lawsuits, including two short-term-use cases, and has been found liable for punitive damages, which are not covered by insurance, in each of those cases. Nonetheless, the lack of definitive proof linking short-term use of Vioxx to an increased risk of heart attack and stroke has kept Merck on the offensive and putting plaintiffs to their proof.

Now, however, that confidence has to have been shaken by the results of a Canadian study published in the Canadian Medical Association Journal. That study analyzed data on 114,000 patients and reported that 239 people in Quebec, 66 and over, suffered heart attacks while taking Vioxx between 1999 and 2002.

None of the Vioxx users had a history of heart attack. The Celebrex users did not exhibit any such statistical increase in heart attack risk.

An analysis of the data indicates that over 25% of those people had their heart attacks within two weeks of their first prescription for Vioxx. The team found that “among elderly users of predominantly low doses of these agents, short-term use of rofecoxib is not without risk, and that risk of MI [heart attack] is not restricted to continuous users nor accentuated with longer-term use."

Thus, the researchers see the need for early monitoring of COX-2 side-effects as well as continued monitoring of patients after the discontinuance of the medication. Some 30,200 Vioxx and 45,000 Celebrex users were studied for about 2 ½ years.

Of the 239 heart attacks in Vioxx patients, 65 took place within only 9 days of starting Vioxx therapy.

Plaintiffs’ attorneys see the Canadian study as a major setback for Merck’s defense strategy that will make even the shortest-use cases more viable and far less defensible. It could also prompt Merck to reconsider its position on settlement.

Study Finds Vioxx Dangers Occur Earlier Than Expected

Wed, 03 May 2006 00:00:00 -0700

Researchers report that heart risks from the withdrawn painkiller Vioxx occur much earlier than had been expectec. Twenty-five percent of heart attacks occurred within the first two weeks of use, a new study found.

A new study led by Queen's University researcher Linda Lévesque shows that heart attacks related to the use of Vioxx a drug once popular for the treatment of pain and inflammation can occur within the first two weeks of use.

A quarter of patients who suffered a heart attack while taking Vioxx did so within the first two weeks of their first Vioxx prescription, said Lévesque, of Queen's Department of Community Health and Epidemiology.

"This demonstrates that cardiovascular risks from taking Vioxx may occur much earlier than previously believed," she said. Conducted with McGill University researchers James Brophy and Bin Zhang, the findings appear on-line in the Canadian Medical Association Journal.

"Our previous study on COX-2 inhibitors, which included Vioxx and Celebrex, evaluated whether there was an increased risk of heart attack while taking these medications; the answer was yes for Vioxx," explained Lévesque.

In the current study, funded by the Canadian Institutes for Health Research (CIHR), the pattern of cardiovascular risk in Québec seniors was assessed over a three-year period.

The additional cardiovascular risk actually decreased with longer duration of use, suggesting that the period of highest susceptibility for most people taking Vioxx may occur earlier than previously believed. The study also documents that cardiovascular risk returns to normal within one month of stopping the drug.

Vioxx was voluntarily withdrawn from the market on September 30, 2004, after a study showed that it doubled patients' risk of heart attacks and strokes after 18 months of use.

This study is the first to specifically address the question of the timing of cardiovascular risk associated with COX-2 inhibitors.

Vioxx Study Mars Merck

Wed, 03 May 2006 00:00:00 -0700

Canadian researchers say older people who took the Merck pain reliever Vioxx for the first time had an elevated risk of an initial heart attack within two weeks of taking the drug.

The study's results, which contain a number of caveats, clash with Merck's assertion that Vioxx-takers had a heightened risk of cardiovascular problems after taking the drug for more than 18 months.

"A small proportion of patients using rofecoxib for the first time had their first myocardial infarction shortly after starting the drug," researchers say in an online version of the Canadian Medical Association Journal published Tuesday. Rofecoxib is the generic name for Vioxx. Myocardial infarction is the scientific term for a heart attack.

Merck questioned their methodology of searching past medical records an observational study rather than conducting a randomized clinical trial.

"While we have not seen the results of the specific study, it is important to remember that this is an observational study," the company said. "Merck & Co. continues to believe that randomized clinical trials provide stronger evidence than observational studies about the efficacy and safety of medicines."

Merck removed Vioxx from the market in September 2004, citing the results from a company-sponsored clinical trial that showed the drug could lead to heart injuries after being taken for more than a year and a half.
Observational Studies

Before Merck pulled the drug, "the data from placebo-controlled clinical studies demonstrated no increased risk for Vioxx compared to placebo," the company said.

In the past, Merck has criticized observational studies. Merck used this argument in August 2004, when it disputed the findings of a Food and Drug Administration study that said Vioxx users had a higher heart-attack risk than users of Celebrex, a Pfizer drug that's still on the market. Vioxx and Celebrex are called COX-2 inhibitors.

The Canadian researchers say first-time users of Celebrex experienced a slightly higher but statistically insignificant increase in their risk for a first heart attack.

The FDA now requires a black box warning, its strongest alert, on Celebrex and other prescription pain relievers to alert patients about the increased risk of cardiovascular problems.
Measuring Risk

The risk of a first heart attack among people 66 years old and older was highest among first-time users of Vioxx within six to 13 days of taking the drug, Canadian researchers say. The median was nine days.

These findings were considered statistically significant by the researchers at McGill University in Montreal and Queen's University in Kingston, Ontario. Among so-called prevalent Vioxx users, there was no statistically significant increase in risk. The researchers define a prevalent user as someone who had at least more than one prescription for the drug.

In fact, they say the risk of heart attacks among elderly Vioxx users "appears to decrease over time, despite repeated exposure, presumably owing to the depletion of susceptible people."

The Canadian study will no doubt provide ammunition to attorneys who are representing plaintiffs suing Merck for personal injury or monetary losses related to Vioxx. The company is defending itself against 11,500 personal injury lawsuits and 190 class-action suits. The next trial starts in early June in New Jersey. A trial in California is set for later next month.

Researchers in the Canadian study used a computerized database of public health records from the province of Quebec between January 1999 and June 2002, assessing nearly 114,000 people. They found 3,708 Vioxx users who met the study's guidelines, as well as 5,598 Celebrex users and 16,680 people who didn't use the drugs. The average age was just over 78.

They found 239 current Vioxx users who had a heart attack, including 65 who took the drug for the first time. They found 287 current Celebrex users who had a heart attack, including 57 first-time users of the drug. The placebo group had 793 heart-attack patients.

The key figure is the heart-attack rate. The control-group's ratio is expressed as 1.00. The ratio for first-time Vioxx users is 1.67, which researchers say is statistically significant. However, they say prevalent Vioxx users had a 1.17 ratio, which is statistically insignificant.

The heart-attack ratio for first-time Celebrex users is 1.29, which researchers say is statistically insignificant. The 0.97 risk ratio for prevalent Celebrex users also is statistically insignificant.

"Although we cannot directly compare our results to those of randomized trials, particularly in view of the older age of our study group, we nonetheless demonstrate the presence of an early risk" of acute heart attack for Vioxx, the researchers say.

Even though the results "provide no conclusive evidence of an increased risk" of heart attacks for Celebrex users, they say "further definitive studies are required."

The researchers note that their work has some limitations. For example, they lacked information about patients' personal health habits, such as smoking, obesity, physical activity and their family history, and their socioeconomic status. These factors can affect one's risk of having a heart attack, but they say "several investigators have demonstrated that, in the context of assessing the risk of [heart attack] , unmeasured risk factors result in no or negligible bias."

In addition, they were unable to determine the patients'use of over-the-counter pain relievers such as ibuprofen. But they said "this source of bias is likely to be negligible, thus leading to an underestimation of the true risk." They cited a previous study they conducted as the source for this assertion.

Painkiller may double risk of heart attacks

Wed, 01 Mar 2006 00:00:00 -0800

A drug used to treat thousands of patients in Britain for chronic pain in conditions such as arthritis has been linked with a doubling of the risk of heart attacks, according to a new study. The drug, Celebrex, is the third drug of its type to raise safety concerns.

Vioxx was withdrawn by its makers two years ago because of cardiovascular complications and Bextra was withdrawn last year because of skin reactions.

In 2004 about 2.5 million people were using Celebrex, but the numbers are known to have reduced substantially since concerns about the drugs were raised.

In the latest study, when researchers pooled the evidence from four existing studies which compared Celebrex with a placebo, they found that it was associated with a 2.26-fold increase in heart attacks.

The studies involved 4,422 patients who had taken the drug for at least six weeks.

A second analysis of 12,780 patients in six other studies suggested the drug gave a 1.88-fold increased risk of heart attack when compared with other pain killers including ibuprofen, paracetamol and diclofenac.

Celebrex, or celecoxib, is one of a class of drugs called Cox-2 inhibitors which were hailed as a breakthrough in the treatment of severe pain.

Traditional treatments like aspirin and ibuprofen are linked to stomach bleeding but the Cox-2s avoided this potentially serious side effect. Celebrex continues to be licensed for pain but doctors are advised to use the lowest effective dose, to avoid long term treatments and not to prescribe it for patients at risk of cardiovascular disease.

Some laboratory research has suggested that Cox-2s may create an imbalance that favours blood clotting and narrowing of blood vessels.

The latest study, in the Journal of the Royal Society of Medicine, adds to the debate over the safety of Cox-2s.

Prof Richard Beasley, of the Medical Research Institute of New Zealand, said yesterday: "Our evidence shows an increased risk of heart attack in patients taking celecoxib.

"Drug regulatory authorities urgently need to re-examine the assessment of the drug in light of these findings."

A spokesman for the manufacturers, Pfizer, said the study sample was small and that the regulatory authorities had carried out extensive studies on Celebrex of their own.

"They were looking at a relatively small sub-set of data. We would point to the combined analysis by regulatory authorities that looked at 40,000 patients.

"This showed a risk similar to older therapies like ibuprofen.

''The other point was that the dose given was above the recommended dose for the majority of cases."

The spokesman said many patients had been given an 800mg dose when the licensed dose is 200mg to 400mg daily.

Pfizer is starting a new long term trial of Celebrex.

Analysis: Celebrex ups heart-attack risk

Tue, 28 Feb 2006 00:00:00 -0800

A meta-analysis released Tuesday indicates Pfizer's Celebrex increases the risk of a heart attack by over two-fold and experts are calling for regulatory authorities to respond promptly to the new findings.

"It's an important finding that regulators need to consider in future prescriptions of this drug," Kamran Abbasi, editor of Journal of the Royal Society of Medicine, where the study was published, told United Press International.

Asked if he thought Celebrex should be taken off the market, Abbasi said, "I'm not saying that." But he added, "This is new data suggesting the risk profile of myocardial infarction is somewhat similar to the risk profile of Vioxx and we know what happened with that, so we need to be careful with this drug."

Merck withdrew Vioxx from the market in 2004 after it was linked to an increased risk of heart attacks and strokes.

Richard Beasley, the principal author of the study and a professor at New Zealand's Medical Research Institute, also thought regulatory officials should take a closer look at Celebrex.

"Our evidence shows an increased risk of heart attack in patients taking celecoxib," Beasley said. "Drug regulatory authorities need to urgently re-examine the assessment of the drug in light of these findings."

Beasley noted the myocardial infarction risk with Celebrex seen in his meta-analyses is similar to a 2.24-fold increased risk with Vioxx that was reported in a separate meta-analysis.

"It will be interesting to see if the drug regulators tighten restrictions and whether celecoxib is now withdrawn as occurred with Vioxx," he added.

However, some experts think the findings are consistent with what was already known about COX-2 inhibitors.

"I don't think this is a huge increment in our knowledge but it does continue to support the notion that there is some potential concern with COX-2 inhibitors and cardiovascular events," David Harrington, a professor in the section on cardiology at Wake Forest University School of Medicine, told UPI.

"At this point, I don't see this as sufficient grounds to change what we previously recommended about COX-2 inhibitors," added Harrington, who also serves as a spokesman for the American Heart Association.

Pfizer criticized the meta-analysis design of the study and pointed out that previous studies had not found an increased risk of heart attacks in Celebrex patients.

"It's not a well-designed study," Pfizer spokeswoman Cathy Cantone told UPI. She also noted that Celebrex had been studied in more than 40 randomized, controlled trials involving nearly 45,000 patients. Of the nearly 25,000 people who took Celebrex, the drug was not associated with an increased risk of heart stroke or cardiovascular deaths when compared with those who received nonspecific NSAIDs.

In the study, Beasley's team conducted two meta-analyses of 10 studies involving Celebrex. In the primary meta-analysis, four trials with more than 4,400 patients were reviewed and the researchers found a 2.26-fold increase in myocardial infarction in patients treated with Celebrex compared to those on placebo. There was no significant increase in risk in composite cardiovascular events, cardiovascular deaths or stroke in the Celebrex patients.

The secondary meta-analysis included six studies involving a total of 12,780 patients treated with placebo, diclofenac, ibuprofen, paracetamol or Celebrex. The Celebrex patients had a 1.88-fold increased risk of myocardial infarction.

The study comes on the heels of a Pfizer-funded study released last week that found no increased risk of cardiovascular or cerebrovascular problems in Celebrex patients compared to those who received naproxen or diclofenac.

However, that study, which is called SUCCESS-I and appeared in the March issue of the American Journal of Medicine, was not designed to look at those issues and Pfizer backed away from giving Celebrex the all clear. Instead, the company said it was waiting on the results of the PRECISION trial, which is slated to begin later this year.

There are other COX-2's in the pipeline, including one GlaxoSmithKline is developing and Novartis' Prexige, that could offer some competition in the coming years, but some analysts think Celebrex will likely retain the predominant share of the market if it is not withdrawn.

Trial Date for Celebrex Suit Set for June

Mon, 27 Feb 2006 00:00:00 -0800

A judge set a June 6 trial date for a lawsuit filed by a woman who claims the arthritis medication Celebrex was to blame for a stroke she suffered last year.

Barring delays, plaintiff's attorneys said Monday the trial could be the nation's first over the popular pain medicine by Pfizer Inc., which projected more than $2 billion in sales for Celebrex this year.

Rosie Ware contends Celebrex was to blame for a stroke she suffered a year ago at age 53. She claims Pfizer and companies it has since purchased understated the risks of the drug and failed to warn consumers of possible side effects.

An attorney for Ware, said about 450 lawsuits have been filed over Celebrex.

A Pfizer spokesman did not immediately return a phone call seeking comment. The drug's Web site includes a warning that Celebrex may increase the risk of stroke or heart attack in some people.

Celebrex is part of a class of drugs called cox-2 inhibitors. It is the only one of its type remaining on the market after Merck & Co.'s Vioxx and Pfizer's Bextra were withdrawn because of safety concerns.

Merck withdrew Vioxx in September 2004 after a study showed it doubled patients' risk of heart attacks and strokes after 18 months of use. The company now faces more than 9,600 lawsuits over Vioxx.

Pfizer is funding a study to determine whether Celebrex leads to more heart problems than other pain relievers.

Strange Goings On at the Cleveland Clinic: Mere Coincidences or Something Far More Problematic?

Mon, 19 Dec 2005 00:00:00 -0800

If you like playing the game “connect the dots,” you might find this one very interesting:

2001 – Drs. Eric Topol and his associate (and subordinate) at the prestigious Cleveland Clinic, Steven Nissen, jointly attack COX-2 inhibitors and especially Vioxx The concerns arising out of the VIGOR study were crystallized by Topol, Nissen, and Debabrata Mukherjee in JAMA in their review paper specifically highlighting the cardiovascular side-effect profile of COX-2 inhibitors. On August 22, 2001 a study published in Journal of the American Medical Association by Drs. Topol, Nissen, and Mukherjee indicated that Vioxx was linked to a 200% increase in blood clots, heart attacks, and strokes based on their review of previous clinical trials.

2004 – Vioxx is pulled from the market and Dr. Topol goes on a relentless attack along the lines of “I told you so” in articles and comments such as the one to the Washington Post (10/1/04) where he stated that Merck’s action was “the right decision about three years too late. This is the sort of thing that Merck should have studied earlier, but they were too busy refuting the warning signs.”

2005 – Vioxx court trials begin and Dr. Topol remains adamant about the cardiovascular risks posed by Vioxx. He is the vocal face of the Cleveland Clinic in the COX-2 saga and certainly the last person in the world Merck or Pfizer would ever want to rely on as a last hope to salvage the multi-billion dollar market for Vioxx or Celebrex.

2004-2005 – Dr. Nissen remains uncharacteristically silent especially in light of his long-standing criticism of the COX-2 inhibitors and Vioxx.

November 2005 – Under subpoena in the first federal Vioxx trial, Dr. Topol pulls out all the stops and offers a three-hour videotaped deposition (much of which was shown to the jury) attacking Vioxx as a dangerous drug from a cardiovascular standpoint and accuses Merck of engaging in scientific misconduct, suppressing clinical evidence and stifling medical discourse as it promoted the painkiller. He also calls certain aspects of Merck's behavior "repulsive" and "appalling." The deposition is shown to the jury on Saturday, December 3, 2005.

December 8, 2005 – Less than a week after his devastating anti-Vioxx, anti-Merck testimony is shown to the jury (and in the midst of the NEJM accusation that Merck manipulated the outcome of the VIGOR study by deleting data relating to at least three heart attack-related deaths) the Cleveland Clinic suddenly announces that Dr. Topol has been stripped of his prestigious position as chief academic officer of the Clinic's medical college. This significant demotion at a time when the Clinic was thrust into the public eye by Dr. Topol’s highly consumer-friendly testimony is described as nothing more than part of a broader administrative reorganization making his “position was no longer needed.”

December 9, 2005 – Dr. Topol states: “The hardest thing in the world is just telling the truth, to do the right thing for patients, and you get vilified. No wonder nobody stands up to the industry.”

December 13, 2005 – Pfizer announces a $100 million study will be launched into the safety of its own drug, Celebrex. Amazingly (or maybe not so amazingly at that) the Cleveland Clinic is to conduct the study and leading the research will be none other than Dr. Nissen himself.

With Celebrex as the only COX-2 inhibitor remaining on the U.S. market, the multi-billion dollar blockbuster will either have the field to itself or be declared no worse than its sister-drugs Vioxx and Bextra. (Prior studies have already indicated that Celebrex was probably the least risky of the COX-2s from a cardiovascular risk profile.)

The $100 million study is little more than a prudent investment by Pfizer. It makes the world’s biggest pharmaceutical company look good from a consumer standpoint. The outcome is thus, anticlimactic. COX-2s will either be shown to be dangerous as a class, which is what most experts already think now, or Celebrex will be vindicated as the safest of the three drugs and remain the only COX-2 on the market.

And, all of this (and $100 million of Pfizer’s money) is being placed in the hands of the Cleveland Clinic and Dr. Nissen.

Dr. Eric Topol has been Provost, Cleveland Clinic Lerner College of Medicine, Chief Academic Officer and Chairman, Department of Cardiovascular Medicine, and Professor of Medicine and Genetics, Case Western Reserve University. He was appointed to the Cleveland Clinic in 1991 after a f ellowship at Johns Hopkins Hospital, an internship at University of California-San Francisco School of Medicine, and a residency at University of California-San Francisco School of Medicine. He attended University of Rochester School of Medicine and Dentistry in Rochester , New York . He is a specialist in interventional cardiology, thrombolytic agents, arterial biology research, and restenosis.

Dr. Steven Nissen currently has no supervisory position or department level chairmanship at the Cleveland Clinic. His appointment to the Clinic was in 1992 after a fellowship at the University of Kentucky Chandler Medical Center, an internship at University of California Davis Medical Center, and a residency at the University of California Davis Medical Center. He attended the University of Michigan Medical School. His specialties include intravascular ultrasound, digital angiography and computer image processing, and coronary intensive care.

It seems quite odd to many observers that the doctor with the superior qualifications would have his leadership position done away with as part of an administrative reorganization making that position “no longer needed” at a time when he would be the ideal person to lead the independent study of Celebrex.

Dr. Topol, however, is hardly the type of professional who could be expected to play a subservient or submissive role and that could have made his participation in the study problematic for his superiors who did not need added attention at a time when the Clinic’s independence and credibility are being questioned.

The prestigious Cleveland Clinic Foundation is a prominent medical center regarded as one of the nation's best. Over the years, however, The Clinic’s need to cultivate a workable relationship with the pharmaceutical companies and medical device manufacturers that fund independent studies and other programs became more and more at odds with Dr. Topol’s consumer-oriented image as a crusader against potentially dangerous drugs and their manufacturers.

Dr. Topol’s recent criticisms extended to drugs other than Vioxx. His candor, however, while admired by his supporters is viewed as quite unscientific to his targets and his detractors. His demotion also came at a time when his ongoing dispute with Dr. Delos Cosgrove had become a distraction at the Clinic.

Dr. Cosgove is Chief Executive Officer, Chairman of the Board of Governors, CCF. His appointment to the Cleveland Clinic came in 1975 following an internship at the University of Rochester-Strong Memorial Hospital and residencies at Children's Hospital of Boston, Massachusetts General Hospital, and University of Rochester-Strong Memorial Hospital. He attended University of Virginia School of Medicine Charlottesville and specializes in the surgical treatment of thoracic and cardiovascular diseases, mitral and aortic valve repair, minimally invasive valve surgery, thoracic aneurysms, homografts, use of alternative conduits in coronary artery surgery, and blood conservation.

Dr. Topol has, for now, retained the position of chairman of cardiovascular medicine at the Clinic, but his demotion has drawn attention to the mounting tensions between the Clinic's research mission and its deep ties to the businesses that finance that research. This rift may lead to Dr. Topol’s eventual departure from the Clinic.
The unrest at the Cleveland Clinic is far more than simply a power struggle between Drs. Topol and Cosgrove, however. It is symptomatic of the continued controversy created by the many longstanding corporate ties at the clinic. Those business links involve staff doctors, researchers, Dr. Cosgrove, and the Clinic's board.
The potential for conflicts of interest at the Clinic is illustrative of the way pharmaceutical and medical device companies and the investment community work closely with medical researchers and doctors to develop and promote new medicines and technologies.

Such relationships raise concerns about potential conflicts of interest that could unduly influence medical decisions as to treatment selections or even bias the results of medical research itself.
The pharmaceutical and medical device industries often find themselves in conflict of interest situations when dealing with “independent” research facilities, the FDA, and when releasing critical data and information about specific drug trials, adverse reactions, defects, and malfunctions.

These industries are bound by federal law and ethical standards to be forthcoming and honest about all relevant details concerning their products, even if unfavorable. Yet, exhibiting remarkably human-like behavior, they often withhold, misrepresent, delay, and otherwise improperly manipulate negative information in order to minimize or avoid harmful financial and legal consequences.

The recent revelations concerning Merck’s alleged manipulation of the VIGOR study by deleting critical data concerning cardiovascular-related deaths are but a window into a world few people are aware even exists.
That world, however, is replete with situations where pharmaceutical companies have: (a) ghostwritten medical journal articles relating to drug safety and trials; (b) delayed the completion of market studies and the subsequent release of the data related thereto; (c) prevented full disclosure about drug trials; (d) withheld important data from the FDA and the public; (e) engaged in misleading, improper, and false advertising campaigns; and (f) pressured the FDA and research facilities to take retaliatory actions against employees who expressed opinions detrimental to a drug or device under review or study.

Fast-track approvals, which are usually based on short-term testing of small test groups, have had disastrous results when used for drugs which are specifically designed for long-term or lifetime use by large segments of the population.

Medical device manufacturers are no more credible or trustworthy than their drug manufacturing counterparts and have been caught engaging in similar bad acts.

Some of the more egregious recent examples of this type of objectionable behavior include a study published in the Journal of the American Medical Association (JAMA) in 2004 that found 65% of findings of harmful effects were not fully reported in medical-journal articles. Results are often “cherry-picked” so that only the positive data is published.

The JAMA study also found that 62% of trials had at least one piece of data or one result that was changed, added, or omitted to make the drug appear better.

Recently, Eli Lilly came under scrutiny for suppressing reports relating to the potential increased risk of suicide risk suspected during early clinical trials. Current clinical trial data that has confirmed this elevated suicide risk.
One trial showed that 3.7% of Prozac users attempted suicide while less than 1% of participants on non-SSRI depressants exhibited the same behavior. Thus, it is reasonable to assume that had there been full disclosure of the early trial data and reports, lives could have been saved.

Johnson and Johnson’s heartburn drug Propulsid has been linked to 80 heart-related deaths and 341 injuries. Despite the adverse effects associated with the drug, Johnson and Johnson did not conduct safety studies and pushed to keep Propulsid on the market. Even with strong black-box warnings on the drugs label, Propulsid was prescribed inappropriately to both adults and children.

After five years of reported problems, Propulsid was pulled from the market in 2000. In 2004, Johnson and Johnson agreed to pay up to $90 million to settle pending claims relating to deaths and injuries from Propulsid.
In the past few years, the FDA has issued dozens of warning letters to pharmaceutical manufacturers. The FDA Division of Drug Marketing, Advertising and Communications has about three dozen employees to review 30,000 to 40,000 Direct-to-Consumer (DTC) ads each year. Lester M. Crawford, then Acting Commissioner of the agency noted that “our patience is sometimes worn thin” by all the advertising claims.

In another shocking disclosure, Adrienne Fugh-Berman, a professor of alternative medicine at Georgetown University, claimed that she was asked to write an article for AstraZeneca about the adverse interactions associated with the combination of Coumadin, a blood-thinner, and dietary supplements and medicinal herbs. AstraZeneca hoped that this information about Coumadin would help them begin to market their own experimental blood-thinner, Exanta.

Fugh-Berman claimed that AstraZeneca then sent her the completed article with her name already on it, before she agreed to write anything. AstraZeneca denied the charge. Later on, Fugh-Berman was asked to review a paper for a medical journal which turned out to be the same paper she was previously asked to pass off as her own.

When the FDA established an accelerated-approval program for new drugs in 1992 it required pharmaceutical companies to continue studying and monitoring a drug even after its market approval. Yet a review by Rep. Edward J. Markey, (D., Mass.) showed that pharmaceutical companies have not completed about half of these studies.
The Markey report indicated that out of 91 studies on 42 different products that were approved from 1993 to October 2004, 46 were completed, 42 were not completed, and three were delayed. Markey argued that “it is outrageous that drug companies and the FDA have been dragging their feet when it comes to conducting required post-marketing studies.” Markey plans to introduce a bill that would allow the FDA to state in a label whether or not a drug has received this accelerated approval so that the public is aware that the drug is still undergoing additional studies.

Significantly, the FDA has funded the fast-track approval program with hundreds of millions of dollars in order to ensure that potential blockbuster moneymaking drugs get to market on an accelerated basis. Thus, FDA has placed itself in a compromising position by accepting these huge sums of money from the pharmaceutical industry to fund the agency’s Office of New Drugs which is now expected to “fast-track” drugs to market.

That division has about 740 employees. Unfortunately, no such funding is given to the FDA for post-approval monitoring of adverse reactions and side-effects by the Office of Drug Safety which only has about 112 employees.
On May 19, Able Laboratories stopped all shipments of its products. Four days later Able recalled its entire product line, suspended all manufacturing and withdrew seven approved applications to market various medications. The massive recall was based on what the FDA itself stated were “serious concerns that they (all of Able’s products) were not produced according to quality assurance standards.”

The FDA eventually revealed that its drastic enforcement action was the result of agency inspectors having found massive record falsification and mismanagement by Able in order to elude FDA detection of several defective medications.

Some of the violations included alteration and falsification of test data and covering up deficiencies by changing results. Able has been effectively put out of the pharmaceutical business as a result of its highly improper conduct.
On July 13, the FDA issued and extensive warning to Hitachi Medical Systems America, Inc. for serious reporting violations and problems with respect to its MRI and PET equipment. The warning followed inspections of Hitachi’s medical device manufacturing facilities by an FDA investigator with respect to the magnetic resonance imaging (MRI) systems manufactured by Hitachi Medical, Tokyo, Japan which are medical devices as defined in section 201(h) of the Federal Food, Drug and Cosmetic Act (the Act).

The above inspection revealed that Hitachi’s devices are misbranded in that the company failed to furnish material or information required under the Act and the Medical Device Reporting (MDR) Regulation. Specifically, Hitachi had received complaints relating to four separate events for which it failed to submit an MDR to the FDA within 30 days of receiving information that the devices may have caused or contributed to a death or serious injury.

On May 24, Guidant Corporation disclosed for the first time that it had waited three years before disclosing it had been aware of the electrical problem that had caused some 28 of these defibrillators to malfunction. The revelation came in the form of an alert to physicians which was not issued until Guidant learned that The New York Times was about to publish a story on the defibrillator. There is no doubt among experts that the delay probably caused unnecessary deaths.

When the FDA held hearings in February of this year supposedly to determine if the COX-2 inhibitors were safe enough to remain on the market, more signs of a system with widespread conflicts of interest became disturbingly clear.

Of the 32 government drug advisers who would vote on the issue, 10 had consulted for Merck (Vioxx) or Pfizer (Celebrex and Bextra) in recent years.

When the votes were tallied, the results were shocking to many but not to those who decry the cozy relationship between “independent” researchers, the FDA, and the industries that are supposed to be under scrutiny.
While the committee voted unanimously that all of the drugs significantly increased the risk of heart attack and stroke, Vioxx, a drug pulled from the market by its own manufacturer (Merck) only 3 months before miraculously rose from the ashes on the wings of a 17-15 vote. (Without 9 of the 10 “questionable” votes going in favor of the drug, however, the committee would have voted 14-8 to ban Vioxx).

Bextra, a drug which had even more serious risks associated with it than Vioxx, survived by a margin of 17-13-2 (abstentions). (That vote would have been 12-8 against Bextra without 9 favorable votes from the 10 advisers in question). Bextra was pulled from the market less than two months later.

Celebrex survived by a 31-1 margin (even though the evidence against it was equally compelling). (The vote still would have been an amazing 21-1 in favor of Celebrex without the 10 “interested” voters).

Although two of the three drugs have been pulled from the market and the third is about to undergo a major safety study, the panel merely recommended all COX-2 inhibitors carry “black box” warnings.

Needless to say, the vote was met with shock and outrage by activists, medical experts, and researchers alike. Several highly reputable news agencies like CBS News, The New York Times, and Forbes, for example, also questioned whether the panel had been “stacked” in favor of the pharmaceutical companies with advisers who had significant “conflicts of interest.”

Undue influence has often been exerted in ways that have compromised the impartial functioning of the FDA and its researchers and doctors.

In 1997 Rezulin was approved to treat Type 2 diabetes. The drug, known generically as troglitazone, was made and marketed by Parke-Davis, a division of Warner-Lambert Company of Morris Plains, New Jersey.
Rezulin was removed from the market by the FDA in March of 2000 as a result of having been linked to a mounting number of cases of serious liver damage and death. The drug had already been removed from the market in England in December of 1997 where officials have refused to allow its reintroduction.

Only eight months after Rezulin was marketed in the United States, the FDA announced that the drug had been linked to illness and death from liver failure. For this reason, the FDA recommended frequent monitoring of liver function in patients taking Rezulin.

Significantly, these problems had been apparent while the drug was being tested according to Dr. Anne Peters, an endocrinologist at the University of California at Los Angeles. Dr. Peters noted that the abnormal test results were so extreme they should have been regarded as a "red flag."

Dr. Peters, and others, believed that Rezulin should have been marketed from the beginning with strong warnings and the requirement that those taking the drug have frequent tests of liver function. Instead, the drug was marketed without any recommendation for liver monitoring.

Unfortunately, the injuries and deaths continued. Surveys showed that few patients were being properly monitored. Labeling changes ordered by the FDA did nothing to remedy the situation and soon, serious divisions developed within the agency itself.
By the beginning of 2000, four senior FDA physicians as well as Dr. Robert I. Mishbin, the FDA Medical Officer most closely involved with the government's approval and continued support of Rezulin, were strongly urging its withdrawal from the market.

In fact, in a January 24, 2000 e-mail to his superiors, Dr Mishbin stated: "I see no reason why any well-informed physician would continue to prescribe [Rezulin]." In warning that "additional cases of preventable liver failure" may occur, Dr. Mishbin also stated that he did not see "any reason why FDA should delay in taking steps to remove [Rezulin] from the market."
The FDA's response was to threaten Dr. Mishbin with disciplinary action or dismissal from federal service.
Although the director of the FDA's drug review center, Dr. Janet Woodcock claimed in a March, 2000 prepared statement that the FDA still believed the benefits of Rezulin to outweigh its risks, a member of the FDA Advisory Committee stated that he was "not surprised" to hear of the dramatic increase of reported liver-failure cases associated with the drug.

Moreover, even long before Dr. Mishbin's change of position, two other FDA physicians had raised serious questions concerning Rezulin. In October, 1996, FDA Medical Officer, Dr. John L. Gueriguian recommended Rezulin not be approved because of potential liver and heart toxicity.

Dr. Gueriguian was the FDA Medical Officer initially in charge of reviewing the Rezulin New Drug Application (NDA). He was a twenty year veteran of the FDA, but was removed from the project in November, 1996, only weeks before the FDA's Medical Advisory Board was set to consider whether to recommend approval of the drug.

The removal came at the request of Warner Lambert, ostensibly because he had used intemperate language in describing the safety and efficacy profiles of the drug. Significantly, this medical Officer had concluded that Rezulin was no more effective in treating diabetes than other drugs already on the market yet it had potential hepatic (liver) and cardiac (heart) side effects.

That same month, Dr. Gueriguian was stripped of further involvement in reviewing Rezulin and his negative review purged from agency files.

In 1999, Dr. David J. Graham, a senior FDA epidemiologist, publicly warned the agency's Advisory Committee that every Rezulin user was at risk for sudden liver failure. In fact, Dr. Graham presented data indicating that, even with monthly monitoring, Rezulin patients still ran the risk of spiraling into sudden liver failure.

Dr. Topol, himself caught up in the problem created by these relationships, announced he would cut all ties to industry, which included relationships with Eli Lilly, deCode Genetics, and the Medicines Company notwithstanding that many doctors at the Clinic and elsewhere have similar consulting deals.

"I think there's a real problem in academics today," he told The New York Times in January 2005. "There's a very close-knit relationship with industry, and it's too close when any individual can derive a profit from that relationship."

A recent survey involving 3,247 scientists who were based in the United States and who had received funding from the National Institutes of Health revealed that about 33% of the participants stated that, within the previous three years, they had engaged in at least one practice that could get them into trouble.

The types of questionable conduct included circumventing minor aspect of rules for doing research on people (8%) and ignoring another researcher’s use of flawed data or questionable interpretation of data (about 13%). Less than 2% admitted falsifying data, plagiarism, or ignoring major aspects of rules governing studies with human subjects. Surprisingly (or maybe not so surprisingly), almost 16% admitted they had changed the designs, methods, or results of a study “in response to pressure from a funding source.”

The National Institutes of Health (NIH) conducted an internal review with respect to consulting payments from pharmaceutical companies to scientists employed by the agency. Of the initial sample, more than half (44 of 81) admitted to conduct which violated one or more NIH rules.

Of those, 36 were still employed by the agency and were referred for possible disciplinary action. Nine of those 36 were also referred to the HHS Office of Inspector general for further investigation. The 8 who left the agency are not subject to administrative action.
The House Energy and Commerce Committee requested the review after comparing NIH records to consulting agreements maintained by 20 pharmaceutical companies. The Committee found 81 cases between 1999 and 2004 where the agreements were not listed in the NIH records provided to the committee.

Excerpts from the findings of the investigation, provided by NIH Director Elias A. Zerhouni to three members of Congress included the following statement: "We discovered cases of employees who consulted with research entities without seeking required approval, consulted in areas that appeared to conflict with their official duties, or consulted in situations where the main benefit was the ability of the employer to invoke the name of NIH as an affiliation.”

Although Zerhouni requested the release to Congress to be treated as confidential, Committee leaders released it as a matter of compelling public interest.

Thus, can anyone really look at the Pfizer (Celebrex) study involving the Cleveland Clinic (without Dr. Topol in the lead) as purely coincidental and beyond the possibility of bias and conflict of interest? Hardly.

If anyone needs additional evidence of the potential for a problematic outcome to this latest study, consider the Washington Post report of August 5, 2001. That article, entitled “Missing Data on Celebrex” (by Susan Okie), sounds eerily similar to the recent revelation by the New England Journal of Medicine (NEJM) with respect to Merck’s conduct involving Vioxx study data.

“When editors of the Journal of the American Medical Association sent medical expert M. Michael Wolfe an unpublished study on the blockbuster arthritis drug Celebrex last summer, he was impressed by what he read.
Tested for six months in a company-sponsored study involving more than 8,000 patients, the drug was associated with lower rates of stomach and intestinal ulcers and their complications than two older arthritis medicines diclofenac and ibuprofen.

JAMA's editors wanted to rush the findings into print, and Wolfe and a colleague provided a cautiously favorable editorial to accompany it. But in February, when Wolfe was shown the complete data from the same study as a member of the Food and Drug Administration's arthritis advisory committee, he said he saw a different picture.
‘We were flabbergasted,’ he said.

The study already completed at the time he wrote the editorial - - had lasted a year, not six months as he had thought, Wolfe learned. Almost all of the ulcer complications that occurred during the second half of the study were in Celebrex users. When all of the data were considered, most of Celebrex's apparent safety advantage disappeared.

‘I am furious I wrote the editorial. I looked like a fool," said Wolfe, a Boston University gastroenterologist. "But all I had available to me was the data presented in the article.’

JAMA's editor, Catherine D. DeAngelis, said the journal's editors were not informed about the missing data. ‘I am disheartened to hear that they had those data at the time that they submitted [the manuscript] to us," she said. "We are functioning on a level of trust that was, perhaps, broken.’

The study's 16 authors included faculty members of eight medical schools. All authors were either employees of Pharmacia, Celebrex's manufacturer, or paid consultants of the company.

***With inclusion of the later data, ‘the actual difference between Celebrex and [the other drugs] are not as wide as they were at six months," he acknowledged. "But I think in the end, it does show that Celebrex has a superior safety profile.’
***Meanwhile, the JAMA article and editorial have likely contributed to Celebrex's huge sales. ‘When the JAMA article comes out and confirms the hype, that probably has more impact than our labeling does,’ said Robert J. Temple, director of medical policy at the FDA's Center for Drug Evaluation and Research.

James Wright, a professor of clinical pharmacology at the University of British Columbia, said he complained to JAMA after noticing differences between the published report and the data presented to the FDA. He praised the Public Citizen's Health Research Group, a consumer organization, for filing a lawsuit that led to the agency's putting all drug studies presented to its advisory committees on its public Web site.

‘Otherwise, we still wouldn't know this,’ Wright said. ‘We would still be in the dark.'

Why should anyone believe that anything has changed so dramatically that the upcoming study will not be prone to the same misgivings by experts and consumer advocates alike? All of the examples set forth above indicate the possibility of another questionable study is more than just a remote possibility especially with Dr. Topol on the outside looking in - the same Dr. Topol who since he came to the Clinic in 1991 has been responsible for establishing its medical school and significantly enhancing the reputation of its cardiovascular medicine unit.

Dr. Topol has revealed that the Clinic’s conflict-of-interest committee, on which he served, had looked into the financial arrangements of other doctors, including Dr. Cosgrove, as well as the fact that patients at the Clinic were being used as subjects in tests of medical devices made by companies in which the Clinic had financial interests.
One potential conflict at the Clinic involved the chief executive of Invacare a major health care supply company. Invacare conducts about $200,000 a year in business with the clinic and several people with Clinic associations sit on the Invacare board.

They include Dr. Bernadine Healy, the former head of the Red Cross who is married to Dr. Floyd D. Loop, the cardiac surgeon who led the Clinic until he retired last year and was replaced by Dr. Cosgrove. Dr. Healy owns options for 41,570 shares of stock in Invacare, according to a securities filing from earlier this year.

As noted above, Dr. Cosgrove is a cardiac surgeon. He is quite familiar with the role physicians play in industry since his inventions include the Cosgrove-Edwards heart device. The device, marketed by Edwards Lifesciences, is used at the Clinic. The Clinic has refused to discuss how or whether its patients are informed of Dr. Cosgrove's connection to the device.

Last January, The New York Times discussed a number of companies in which the Clinic had a financial interest (including AtriCure, a heart device manufacturer).

On December 16, The Wall Street Journal ran a front-page article about the Cleveland Clinic’s financial ties with Cardio Vention, the maker of a heart-lung machine blamed for the death of a Clinic patient in May 2002. Press releases issued by the Clinic through Dr. Cosgrove that praised the device in April 2002, failed to disclose that Dr. Cosgrove and the Clinic had a financial interest in the company that ceased operations in 2003.

Several Clinic surgeons, including Dr. Cosgrove, were consultants to Cardio Vention and received stock options in the company.

Dr. Cosgrove also has financial interests in a number of other companies doing research at the Cleveland Clinic as a result of his investment in Canaan Partners, a venture capital fund that also backed Cardio Vention.
Many medical ethicists believe that all of these entanglements may call into question the Clinic's reputation as a world-class independent research institution. “All of these pieces of information coming out bit by bit are potentially damaging to the clinic's reputation," said Dr. Mildred K. Cho, a medical ethicist at Stanford University.
Although the clinic claims its board of trustees has appointed an independent group to review the Clinic's conflicts, Dr. Topol has been removed from the conflict-of-interest committee, a position he held by virtue of his leadership role at the medical college.

Thus, as the COX-2 saga continues to unfold (or unravel as the case may be) will the Celebrex study live up to the hype already placed on it by Dr Nissen who has stated: "There's only one way through good science. We know the burden is upon us to do this right."

Independent researchers are to collect and control the results and have offered to make all of them public, not only the final conclusions. None of the top researchers will be permitted to have financial ties to any pharmaceutical company that manufactures painkillers.

The Celebrex study will be called PRECISION, for Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen. Results are expected in about four years. You can sell an awful lot of Celebrex in four years, that’s for sure.

New Study Finds COX-2 Inhibitors Are Not Safer for the Stomach

Mon, 05 Dec 2005 00:00:00 -0800

A new report in the December 3 issue of the British Medical Journal finds that COX-2 inhibitors are just as harmful to the stomach as traditional anti-inflammatory medications like aspirin. This finding would negate the central reason the embattled family of drugs was approved in the first place.

Researchers at the University of Nottingham examined cases of 9,407 patients with upper gastrointestinal events, like stomach bleeding or stomach ulcer, from 367 general practices. 45% of the patients had received traditional non-steroidal anti-inflammatory drugs (NSAIDs), and 10% had received COX-2 inhibitors. Out of 88,867 control subjects, 33% had been given an NSAID, and 6% had been given a COX-2 inhibitor.

It was found that there was an increased risk of stomach problems with both types of pain killers. The risk was significantly higher for the COX-2 inhibitors naproxen, and rofecoxib (Vioxx), and diclofenac (Voltaren). The risk was slightly lower for celecoxib (Celebrex). Celebrex is the only COX-2 inhibitor that is still on the market in the U.S. since the others were pulled as a result of cardiovascular and other potential adverse reactions.

The report authors concluded that even though COX-2 drugs were designed to provide pain relief without the serious gastrointestinal side-effects associated with conventional NSAIDs, "we found no consistent evidence of enhanced safety against gastrointestinal events with any of the new cyclo-oxygenase-2 inhibitors [cox-2 inhibitors], compared with non-selective, nonsteroidal, anti-inflammatory drugs."
Dr. A Mark Fendrick, professor of internal medicine and health management and policy at the University of Michigan, believes that this study illuminates the increased dangers of gastrointestinal (GI) bleeding when a COX-2 inhibitor and aspirin are used together.

According to Dr. Fendrick: "The fact that cox-2 inhibitor drug users had higher rates of adverse GI events than nonusers comes as no surprise to me, Even a drug that might be safer than other alternatives doesn't mean that the drug is completely safe." It is fine to take a cox-2 inhibitor for joint pain and an aspirin for your heart, but “when you combine these two, they really present GI problems."

Another expert, Dr. Eric Matteson, a professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minnesota, believes the study reveals COX-2 inhibitors increase the risk of GI bleeding and ulcers when used in clinical practice. "These drugs were touted as prevention of adverse GI events, which is completely false. There might be some reduction in risk, but it was never prevention."

"In actual practice, the utility of these drugs is very low in terms of reducing the risk for important GI side effects," Matteson said. "This differs from what was found in clinical trials, which is always different from what is seen in actual practice." According to Matteson this study highlights the GI risks of taking any of these drugs. "All NSAIDs increase your risk for stomach problems, including ulcers and bleeding, which can be serious and even fatal. This includes the COX-2 drugs."

Of course, if this is so, all of the hype and expense associated with the COX-2s was for naught and the only ones that benefited from the drugs were (and are) Merck and Pfizer, which have made tens of billions of dollars in profits from Vioxx, Celebrex, and Bextra.

Another caution on Vioxx, Celebrex

Sun, 13 Nov 2005 00:00:00 -0800

Merck's Vioxx, Pfizer's Celebrex and similar painkillers increase the risk of death among patients who have already survived a previous heart attack, especially when taken in high doses, according to data released Sunday at the American Heart Association conference here.

Patients who have heart disease should not use these types of drugs, called COX-2 inhibitors, according to Dr. Gunnar Gislason, a research fellow at Bispebjerg University Hospital in Copenhagen and the lead independent researcher in the study, which was funded by the Danish Heart Foundation and the Danish Pharmaceutical Association.

"These results are a cause for concern but not panic," said Gislason. "If you can avoid them, it makes sense to switch to another type of medication if you have cardiovascular disease."

"We have not yet seen the study," said Merck spokesman Chris Loder, who noted that drug safety is typically established through randomized controlled clinical trials, which is different from the type of study conducted by Gislason. "Randomized controlled clinical trials are the gold standard."

Pfizer executives were not immediately available to comment.

This is the latest in a string of bad news regarding the COX-2 drugs, also known as NSAIDs, once a popular class of painkillers that generated billions of dollars in annual sales. The drugs work by blocking COX-2, an enzyme that inflames the joints, and are generally used as arthritis painkillers.

Gislason's study showed that heart disease patients taking more than 25 milligrams daily of Vioxx, also known as rofecoxib, were five times as likely to die as those patients not taking this type of drug. Those taking a 200 mg daily dose of Celebrex, also known as celecoxib, were 4.2 times as likely.

Merck pulled Vioxx off the market on Sept. 30, 2004 after a clinical study suggested an increased risk of heart attacks and strokes in patients who took the drug for at least 18 months. However, Merck says that clinical study did not establish an increase in the risk of death from using Vioxx. Nevertheless since the withdrawal at least 6,500 lawsuits have been filed against Merck by plaintiffs blaming heart attacks on Vioxx, which made $2.5 billion in 2003, its last full year on the market.

Merck lost the first Vioxx trial in August, a wrongful death suit filed in Houston, and the jury awarded the plaintiff $253 million for the 2001 death of her husband. That award would be capped by Texas law at $26 million, according to plaintiff lawyer Mark Lanier. But Merck won its second trial in Atlantic City, N.J., defeating a plaintiff who blamed Vioxx for his non-fatal heart attack in 2001. The next trial begins on Nov. 28 in Houston, where Merck faces its first federal lawsuit, as part of thousands of lawsuits consolidated through federal court.

Pfizer was able to keep Celebrex, which totaled $3.3 billion in 2004 sales, on the market, but the Food and Drug Administration required the drug to carry a revised label containing a specific warning. Prescriptions have plunged. Gislason's report did not name Bextra, another COX-2 inhibitor from Pfizer that was pulled from the market on April 7, 2005 at the request of the FDA. Bextra sales totaled $1.3 billion in 2004, its last full year on the market.

The Gislason study was based on the medical records of more than 58,000 Danish patients released from hospitals following their first heart attack between 1995 and 2002. Following their release, the patients were treated with Vioxx, Celebrex and "other NSAIDs," according to the researchers.

Many Painkiller Users Not Protected Against Stomach Bleeding

Mon, 10 Oct 2005 00:00:00 -0700

A new study finds that less than a third of patients at high risk for gastrointestinal bleeding while taking NSAID painkillers are being prescribed medicines to prevent that bleeding.

NSAIDs include over-the-counter and prescription versions of aspirin, ibuprofen and naproxen (Aleve), as well as Vioxx and Bextra, which have been recalled, and Celebrex, which is still sold in the U.S.

According to ABC News, doctors have long recognized that long-term use of NSAIDs can raise risks for gastrointestinal bleeding, and guidelines exist to spot patients at high risk. However, many doctors are not giving patients the medicines that can protect them against bleeding, according to study author Dr. Neena S. Abraham, a gastroenterologist at Baylor College of Medicine

NSAIDs are the most commonly prescribed drug in the United States, says Abraham, and upper gastrointestinal bleeding occurs in about 4.5 percent of patients who take NSAIDs over the long term. Those most at risk for bleeding include people over 65, patients who take steroids or anti-coagulants with NSAIDs, and those who take painkillers in an amount exceeding the manufacturer’s recommended dosage.

In their study, Abraham and her colleagues looked at more than 300,000 patients treated throughout the county in 2002. All were prescribed NSAIDs for pain relief, and would also be considered at high risk for upper gastrointestinal bleeding.

Among patients with one or more risk factors, only about 27% were given therapy to counter the risk of bleeding, the researchers found. Among patients with two or more risk factors, the number rose to 40% and therapeutic assistance reached a high of 42% for those with three or more risk factors for bleeding.

The results of the study appear in Gastroenterology 2005.

Merck Loses Vioxx Case

Fri, 19 Aug 2005 00:00:00 -0700

DOBBS: A jury tonight in Texas finding Merck liable for the death of a man who took its blockbuster painkiller drug Vioxx.

The jury awarded his widow more than a quarter of a billion dollars in damages after reviewing evidence that links the drug to an increased risk of heart attack and stroke. This is the first of thousands of Vioxx-related lawsuits slated for trial. Ali Velshi is here now.

Ali, this award is unbelievable.

ALI VELSHI, CNN CORRESPONDENT: It's phenomenal. It's also not like to stand up. The widow of the man who is in question here has actually -- her lawyer said he doesn't expect this award of $229 million in punitive damages to stay because under Texas law, they don't allow it. That 229 is probably going to come down to $2 million.

DOBBS: Do we know what inspired the jury to come up with such a massive number?

VELSHI: The issue is how the drug companies market these drugs. The information was out there that they have risks, but here's the issue. These are competitive drugs to Vioxx.

VELSHI: extra pain killers. And this is the stuff that comes with it. The drug companies say, "we put this out there. This is the information that you need to read." But who reads it? Do we read it? Should we read it? The issue is that Merck marketed this drug with the benefits and focus and the risks.

DOBBS: And a point of fact, Bextra, Celebrex, and Vioxx, Vioxx taken off the market, these for a short period, the FDA ultimately being criticized roundly for permitting these COX-2 inhibitors to be on the market at all. Several scientists saying they're simply not safe. But the lack of safety justified because of the immense pain that apparently some of these drugs, apparently I say underlined, relieve. So it's a remarkable situation.

VELSHI: Vioxx with a $2.5 billion a year drug. Lipitor is a $10 billion a year drug. But these drugs all come with risks, and everybody has to weigh the good against the bad. And the issue is how much information do you need to make that decision.

DOBBS: And Merck's stock, as one might expect, plummeting today.

VELSHI: It took a big hit today. But it took a big hit when they pulled it off the first time. So Merck is a smaller company than it once was.

DOBBS: OK. With 4,000 lawsuits in the wings...

VELSHI: This is where people are worried. Might be up to $50 billion in liabilities some analysts say. We'll find out more as this unfolds.

DOBBS: Indeed we will. Ali Velshi, thank you.

Vioxx Decision

Fri, 19 Aug 2005 00:00:00 -0700

BLITZER: There's breaking news we're following right now in a major drug liability case, a Texas jury only moments ago has just found the giant pharmaceutical company, Merck, responsible for the death of a man who took their now pulled painkiller Vioxx.

Our Business Correspondents Ali Velshi and Allan Chernoff both standing by with details of what has just happened, let's start with you, Allan. What happened?

ALLAN CHERNOFF, CNN SENIOR CORRESPONDENT: Wolf, this is a huge defeat for Merck because on the face it appeared that this actually was a relatively weak case against Merck, the pharmaceutical giant.

You'll recall that Merck had withdrawn Vioxx last year after studies showed it could cause heart attacks or stroke in people who took the drug for more than 18 months.

Well, the person who passed away here back in April of 2000, Bob Ernst, had taken the drug for only eight months and he did not have a heart attack or a stroke according to the coroner. Nonetheless, the jury here has found Merck liable for his death and awarded his widow a total of $253 million, $24 million of that in mental anguish, $229 million of that punitive damages against Merck.

Bob Ernst, the person who passed away, he was a manager at a Wal- Mart, so he did not have a very large salary at all. Nonetheless, a huge victory for the plaintiffs here, Merck suffering a major defeat and this really could open the floodgates for more lawsuits against Merck regarding Vioxx.

There are already about 4,000 lawsuits against the company and this clearly would encourage other people to file suit against Merck, a big defeat for the pharmaceutical company, Wolf.

BLITZER: Allan, stand by.

Ali Velshi has also been following this very important trial. Ali, give us your thoughts on what has just happened.

ALI VELSHI, CNN CORRESPONDENT: I think Allan put his finger on it. This wasn't thought to be as big a deal as it was for Merck because there are a lot more of these lawsuits following it. This is not good news for Merck but it seems to the markets seem to be reacting in a way that expected it.

Allan, one of the things about Texas is the old Fen-Phen trial, the old American Home Products, which has now become Wyeth. There was a $900 million punitive award, punitive damages awarded to the plaintiffs there.

Texas has a law that caps punitive damages. It's typical that this kind of thing would be pared down that the punitive damages of 200-plus million dollars is probably going to be pared back.

CHERNOFF: Sure, most likely that that number would be pared down without question but here clearly the big news is that Merck has lost the case and this was a case that on the surface, again, Merck seemed to have a very simple argument and it clearly would have argued that Bob Ernst simply didn't apply, wasn't one of these people who should have been a victim of Vioxx according to Merck's scientific studies.

But, the jury has clearly gone against Merck and a huge victory for the attorney Mark Lanier. He's a relative young man but considered one of the top litigators in the country and he took this case on several years before Merck had pulled Vioxx from the market. After Merck did pull Vioxx then the flood of lawsuits came in. So, Wolf, again we're going to really see a lot more lawsuits being filed now against Merck. There's no question about that.

BLITZER: Ali, before both of you wind up just remind our viewers about this controversial painkiller Vioxx. Merck on its own voluntarily pulled this painkiller in the face of some studies.

VELSHI: Yes. The issue is how much Merck knew about the dangers associated with Merck with Vioxx. It's a painkiller. It was widely prescribed as an arthritis drug but it was commonly prescribed to people as a sort of a more effective drug than the over-the-counter painkillers that were out there.

Well, what happened is it turns out that after some people suffered heart attacks the investigations led to some understanding that Merck might have known there was a risk and not and as limited as that risk may have been not clearly articulated that risk to people who bought and used the drug regularly. It did become a very popular painkiller.

It's a class of painkillers. There are other ones on the market that were also pulled as a result of it. The issue here is how much pharmaceutical companies have to disclose in terms of the risks that they know of when they market a drug like this, Wolf.

BLITZER: All right, Ali and Allan stand by. We're going to get back to both of you during the course of this program.

And just to recap, a Texas jury has ruled against the giant pharmaceutical company Merck and Company, liable now for $253.4 million damages and other expenses, the result of the once very popular painkiller Vioxx, more on the story coming up.

FDA Gives Celebrex New Warning Label and New Indication

Wed, 03 Aug 2005 00:00:00 -0700

In a bureaucratic mixed message, the FDA finalized a long-anticipated black box warning for the Celebrex (celecoxib) label on the same day that the agency approved the drug for ankylosing spondylitis, a new indication.

In April, an independent panel of advisers convened by the FDA recommended the black box warning for Celebrex and other NSAIDs, including ibuprofen and naproxen. The panel was convened after published reports that Cox-2 inhibitors such as Celebrex increases the risk of cardiovascular events.

Last September, Merck withdrew its popular Cox-2 Vioxx (rofecoxib) from the market after investigators in a cancer-chemoprevention trial reported that long term use of the drug increased the risk of heart attacks and strokes, although it did not increase cardiovascular mortality. Earlier this year, Pfizer, which makes Celebrex, withdrew its other Cox-2, Bextra (valdecoxib), when similar reports surfaced about it. Celebrex is the only Cox-2 remaining on the market.

The Cox-2 cardiovascular risk link prompted researchers to review studies of other NSAIDs, which turned up apparent increased cardiovascular events associated with those drugs as well. The bottom line, the FDA advisory group concluded, was that all the painkillers with the exception of aspirin should receive new labels to reflect the increased risk.

Celebrex's label will recommend that the drug be prescribed at the lowest dose and shortest time possible. The label will also carry a warning that Celebrex should not be used to treat pain associated with heart bypass surgery.

In announcing agreement with the FDA over the new label, Pfizer said the agency approved Celebrex for ankylosing spondylitis, or arthritis of the spine, which affects about 400,000 Americans. With the new indication, Celebrex is now approved for treatment of osteoarthritis, rheumatoid arthritis and as a treatment for familial adenomatous polyposis.

Pfizer Adds Warnings To Celebrex Label

Mon, 01 Aug 2005 00:00:00 -0700

Pfizer Inc. said Monday the Food and Drug Administration added some warnings to the label of its Celebrex pain reliever developed by Monsanto Co.

Pfizer said the label contains a warning of potential cardiovascular and gastrointestinal risks. The label also recommends that Celebrex be prescribed at the lowest effective dose for the shortest period of time.

In February, the FDA recommended that stronger warnings be given to the COX-2 pain relievers, such as Celebrex, as well as to non-steroidal anti-inflammatory drugs, such as ibuprofen and naproxen.

Monsanto's (NYSE: MON) G.D. Searle & Co. pharmaceutical unit rolled out Celebrex in February 1999. In December 2004, Pfizer said Celebrex could increase the risk of heart problems. It later pulled advertising for the drug and pulled another of its pain relievers, Bextra, from the market.

In 2004, Celebrex sales totaled $3.3 billion and Bextra sales totaled $1.3 billion, according to published reports.

The FDA also approved the drug to treat a sixth condition, ankylosing spondylitis, which affects more than 400,000 Americans.

New Study Links Common Painkillers with Heart-Attack Risk

Thu, 09 Jun 2005 00:00:00 -0700

Ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDS) may increase the risk of heart attack, according to research published in this week's BMJ.

Patients should not stop taking the drugs involved, the authors caution, but further investigation into these treatments is needed, they say.

In the biggest study of its kind to date, researchers identified 9,218 patients across England, Scotland and Wales who suffered a heart attack for the first time over a four-year period. Patients ranged in age from 25 to 100.

The investigators looked at the prescribing patterns for these patients, tracking whether and when they had been prescribed NSAIDS. This class of medications, which commonly are prescribed to relieve inflammation and pain, includes ibuprofen, diclofenac (Advil, Motrin, etc.), naproxen (Aleve, Nuprin, etc.), celecoxib (Celebrex) and rofecoxib (Vioxx) plus a host of other less commonly prescribed anti-inflammatories.

Rofecoxib is no longer commercially available, having been withdrawn from the market in 2004. NSAIDS Increased Risk

The findings were adjusted to allow for several other heart-attack risk factors including age, obesity and smoking habits. Importantly, the researchers also adjusted for whether patientd already suffered from heart disease or were prescribed aspirin.

For those who were prescribed NSAIDS in the three months just before the heart attack, the risk increased compared with those who had not taken these drugs in the previous three years, the researchers found. For ibuprofen, the risk increased by almost a quarter (24%) and for diclofenac, it rose by over a half (55%).

The newer generation of anti-inflammatories known as COX-2 inhibitors also were associated with increased rates of first-time heart attack. Those patients who were prescribed the drugs in the preceeding three months were at 21% higher risk of heart attack if taking celecoxib (Celebrex) and 32% increased risk if taking rofecoxib (Vioxx).

'Considerable Implications for Public Health'

Since this study was concluded, rofecoxib was withdrawn due to concerns over heart-attack risk. That makes the impact of this study on patients even more important, say the authors, since those previously taking rofecoxib will have turned to the other anti-inflammatories in greater numbers.

The most significant findings were for the drugs ibuprofen, diclofenac and rofecoxib, say the authors. In terms of "numbers needed to harm" in the 65 and over age group, for those taking diclofenac, one extra patient for every 521 patients was likely to suffer a first-time heart attack.

For rofecoxib, the figure was one patient for every 695 patients; and for ibuprofen, one patient for every 1,005 patients was at risk.

"Given the high prevalence of the use of these drugs in elderly people and the increased risk of myocardial infarction [heart attack] with age, the relatively large number of patients needed to harm could have considerable implications for public health," say the authors.

The nature of this report, an observational study may make it prone to other explanations for the findings, say the authors. "However, enough concerns exist to warrant a reconsideration of the cardiovascular safety of all NSAIDS," they conclude.

Penn Study Points To How COX-2 Inhibitors Can Eventually Lead To Heart Disease

Wed, 25 May 2005 00:00:00 -0700

University of Pennsylvania School of Medicine researchers have found additional evidence that may help explain how selective inhibitors of COX-2 might predispose individuals to heart disease and stroke.

In Circulation Research, they report that a COX-2-derived fatty substance a prostaglandin called prostacyclin controls the blood-vessel response to stresses such as high-blood pressure, thereby further linking COX-2 inhibitors to an increased risk of heart attack or stroke.

This knowledge, along with a growing literature on physiological responses to COX-2 inhibitors, should help in the development of a rational approach to clinical risk management for this class of drugs.

Two randomized trials of COX-2 inhibitorsthe gold standard of clinical evidenceconducted in 2004 at other institutions suggested that risk of cardiovascular disease might increase gradually during continued treatment with drugs such as Celebrex and Vioxx, even in individuals initially at low risk of the disease.

"The risk of heart attack and stroke became progressively evident during treatment with either Celebrex or Vioxx during the APPROVe and APC trials last year," says Garret FitzGerald, MD, lead author of the study published online last week. FitzGerald is the Director of the Institute for Translational Medicine and Therapeutics at Penn.

These studies were designed to determine whether COX-2 inhibitors limited the development of benign growths in the large bowel of patients whoto the best of study authors' knowledgewere at low risk of heart disease. "While the results of these trials are not conclusive, they are compatible with a gradual transformation of increased cardiovascular risk during continued dosing with either Celebrex or Vioxx," says FitzGerald. "We need to determine how this might occur, and whether we can manage this risk by developing tests that reflect the process."

Earlier animal studies by Penn researchers and others showed that suppression of the protective fat prostacyclin, which is made by COX-2, could predispose individuals to a rise in blood pressure which, in turn, can accelerate hardening of the arteries, or atherosclerosis. COX-2 inhibitors such as older NSAIDs have been shown to raise blood pressure in people. In addition, the Penn group has shown in previous studies that shutting down prostacyclin hastens initiation and early development of atherosclerosis.

The current research expands on this notion. R. Daniel Rudic, PhD, and Derek Brinster, MD, and others in FitzGerald's laboratory, report that COX-2-derived prostacyclin also controls the changes that occur in the muscular lining of blood vessels in response to pressure-related changes in blood flow.

They used two animal models to test their ideas. In one, they looked at changes in a blood vessel that had been transplanted into mice of a different genetic make-up; in fact, the model mimicks the events of human organ transplant rejection. Here, they found that they had, in effect, removed a brake on the response of the blood vessel to the challenge of transplantation by deactivating prostacyclin by genetically deleting its receptor.

The result was that muscle cells proliferated dramatically, which normally reduces the openness of the blood vessel. However, the openness of the blood vessel was not changed, through a process of structural reorganization of the blood vessel called vascular remodeling.

In the second model, they reduced blood flow in arteries in the neck and looked at the downstream effects in the blood vessel. This time, instead of suppressing prostacyclin receptor signaling by genetic deletion, they did so by giving a COX-2 inhibitor. Indeed, they saw the same effect.

Cells in the muscular lining of the vessel wall multiplied (just like in the transplant model). Additionally, despite the vessel growth caused by the COX-2 inhibitor, openness of the blood vessel was again preserved. This occurred despite lower blood flow caused by the COX-2 inhibitor. Thus, prostacylin may act to remodel blood vessels to preserve adequate blood flow.

"What is really convincing here is how similarly the two models responded and how the genetics of the pharmacological approach to disrupting the effects of COX-2 had the same effect," says Rudic. In further studiesalso described in the paper and performed in collaboration with Thomas Coffman, of Duke UniversityFitzGerald's group showed that the consequences of shutting down COX-2-derived prostacyclin could be limited, in part, by removing a receptor activated by thromboxane A2, the fatty product of COX-1 in platelets.

This mirrors a similar balancing effect between COX-1 and COX-2, which has been noted in the case of blood clotting, blood pressure, and atherosclerosis. This suggests that suppression of thromboxane with low-dose aspirin could reduce the risk of heart disease if taking COX-2 inhibitors.

These findings suggest that during prolonged dosing with COX-2 inhibitors, several consequences of drug actiona rise in blood pressure, initiation, and early development of atherosclerosis, and now the architectural and functional response of blood vessels to such stresscould all interact in a reinforcing fashion to transform the risk of heart attack and stroke, even in previously healthy individuals. "We need to determine whether these mechanisms are operative in people, and if so, we should be able to develop tests which reflect this process," says FitzGerald.

"This may allow us to detect the small number of individuals at risk of rapidly developing heart disease and stop the drugs before they run into trouble. We could also determine how quickly risk might dissipate on stopping the drugs. Certainly, the development of a rational approach to risk management will be key to giving Celebrex or other COX-2 inhibitors safely, even to healthy patients, for extended periods."

Study: Vioxx, Celebrex Were Widely Overprescribed

Sat, 21 May 2005 00:00:00 -0700

When COX-2 inhibitors were first introduced in 1999, they were promoted as pain relievers, inflammation reducers, and less likely than NSAIDs to cause adverse GI effects. Over the next few years, after being heavily promoted to physicians and the general public, Vioxx and Celebrex became widely used by millions of persons who had little risk of GI bleeding.

The overuse of the COX-2 inhibitors is documented in a study by researchers from the University of Chicago and Stanford University School of Medicine; results were published in the January 24 issue of the Archives of Internal Medicine. Findings of the study, led by Carolanne Dai, MSc, University of Chicago, showed that almost two thirds of the growth in COX-2 inhibitor use from 1999 to 2002 occurred in patients at minimal risk for GI bleeding from NSAIDs.

Researchers looked at data from 2 nationally representative surveys that tracked patient visits to their physicians between 1999 and 2002 and the types of medications prescribed at those visits. The researchers also categorized patients according to their risk of GI bleeding from NSAIDs.

Dai and colleagues found that 73% of patients had either a very low (31%) or low (42%) risk of GI bleeding from NSAIDs and, thus, no pressing medical reason for them to switch to COX-2 inhibitors. However, this was the group in which the greatest growth in COX-2 use occurred. The number of physician visits associated with COX-2 use in these patients increased from 9.5 million in 1999 to 20.9 million in 2002, accounting for 63% of growth in the use of COX-2 inhibitors during that time. Patients most likely to benefit from use of these newer agentsthose with moderate or high risk of GI bleedingaccounted for the remaining 37% increase.

Perils of Pain Relievers Often Disguised In Tiny Type

Sun, 08 May 2005 00:00:00 -0700

If ever there was a classic case of "no free lunch," popular pain control medications are it. There's not one without a potentially serious risk. Yet, far too many people use them carelessly, without adequate attention to dosage and warnings about possible risks.

For over a century, aspirin was the pain drug of choice, until data emerged on the rather large number of bleeding-related deaths this time-honored medicine caused each year. In fact, many pharmaceutical experts say that if aspirin had to go through the Food and Drug Administration's approval process today, it would never make it to market.

Along came some dandy substitutes, now also sold over the counter under brand names and as generics: ibuprofen (Advil, Motrin IB) and naproxen (Aleve). Ibuprofen and naproxen, known as nonsteroidal anti-inflammatory drugs, or Nsaids, can equal or outdo aspirin's action against painful inflammation but at less risk of bleeding.

But they, too, can have serious side effects: They can irritate the gastrointestinal tract and possibly cause ulcers. People who use Nsaids chronically are often told to take an anti-acid drug to protect their stomachs.

This problem opened up a market for a new kind of drug called a cox-2 inhibitor, sold as Celebrex, Vioxx, Bextra and Mobic. These drugs are as good or better than ibuprofen for pain, although as patented prescription medications they greatly multiplied the cost of pain relief.

The cox-2 inhibitors were considered safer because they reduced the risks of bleeding and gastrointestinal damage. And as major money-makers, they were heavily promoted, especially to the millions who need relief for chronic problems.

Alas, these too have come under serious fire as their use mushroomed and evidence emerged linking them to heart attacks and strokes among users already at risk for these problems. With many multimillion-dollar lawsuits looming, Vioxx was the first to be withdrawn from the market, recently followed by Bextra. Both drugs may come back, accompanied by more stringent warnings. Or their cox-2 cousins, Celebrex and Mobic, may join the ranks as drugs gone by.

Problems also accompany other prescription painkillers, like the opioids.

This brings us to an entirely different drug, acetaminophen, long used to counter fever and occasional aches and pains such as tension headaches. But now acetaminophen is being hailed as an excellent first choice for the relief of chronic pain.

Acetaminophen, often referred to by its most popular brand name, Tylenol, has no anti-inflammatory action. Nor does it cause bleeding or gastrointestinal distress. Many pain specialists say it should be considered first for relief for the persistent pain of osteoarthritis and prolonged pain of muscle or joint injuries.

All in all, acetaminophen is a safe drug for children and adults. Despite the many millions of doses taken by Americans each year, few reports of serious side effects emerge when acetaminophen is used in the dosages recommended by manufacturers.

For example, in a study published a decade ago evaluating the experience of 28,130 children who had taken acetaminophen, there was no increased risk of gastrointestinal bleeding, kidney failure, life-threatening allergic reactions or Reye's syndrome, a potential fatal side effect of aspirin when given to children with viral infections.

Acetaminophen is also considered safe for women who are pregnant or breast-feeding, although they are advised to check first with their doctors. And acetaminophen is the pain reliever of choice for those with serious allergies who may be at risk of severe allergic reactions from aspirin and Nsaids.

Perhaps as a testament to its safety, acetaminophen is found not only on its own in a variety of dosages, but also in combination with other medications, over the counter and prescription. If consumers are unaware of its presence in different medications, or if they fail to adhere to cautionary statements about dosages, it is possible to take too much acetaminophen inadvertently.

As with any other medicine, with acetaminophen it is critically important to keep in mind this irrefutable adage: The dose makes the poison.

For example, no one questions the safety of following recommended doses. If you can read the fine print on the label, it will tell you that for adults and for children 12 and older, two 500-milligram tablets or capsules can be taken every four to six hours, as long as no more than eight tablets (a total of 4,000 milligrams) are taken in a 24-hour period unless a physician says otherwise.

Taking more than 4,000 milligrams a day of acetaminophen on a chronic basis can damage the liver of an adult. The danger dose would be far smaller for young children.

It is easier than you may think to take more than 4,000 milligrams a day. With the higher-dose tablets (650 milligrams each) now sold to treat arthritis, you can easily exceed the safety limit if you do not follow the instructions to take two tablets every eight hours, for a maximum daily dose of six tablets in 24 hours, adding up to 3,900 milligrams a day.

Even if you follow these directions, you can exceed the recommended daily dose if you also take another medication say, an over-the-counter cold or flu remedy that contains acetaminophen.

The label on Tylenol Arthritis Pain has a clearly stated warning: "Do not use with any other product containing acetaminophen." But without a magnifying glass, many elderly people who are the most likely users of an arthritis drug would have trouble reading the labels on this and many other medicines like it.

A second warning on acetaminophen says: "If you drink three or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen may cause liver damage."

So, if your liver is already under attack from alcohol, acetaminophen can be that last straw, resulting in liver failure.

This year, the journal Emergency Medicine warned physicians about the hazards of overdoses of acetaminophen. Dr. Shirley Kung and Dr. Kennon Heard wrote that acetaminophen poisoning could often be much worse than it seemed at first.

Nausea and vomiting can progress to complete liver failure in as little as 24 hours unless the problem is promptly recognized and the proper antidote given within 24 hours of a toxic dose. To fully prevent liver injury, the antidote should be given within eight hours.

Each year, more than 100,000 calls related to acetaminophen are made to poison control centers in the United States, and about 150 acetaminophen-related deaths are reported. Some cases result from deliberate overdoses by people trying to commit suicide. But many others are accidental, like the one described in the journal: an 18-month-old child with a fever and cough for three days who had been given acetaminophen every two to four hours.

Other cases result when people whose livers are damaged by other disease take acetaminophen for respiratory infections or pain.

Could Celebrex Survive A Black Box?

Thu, 05 May 2005 00:00:00 -0700

The black box label is the most potent warning in the Food and Drug Administration's arsenal, but it is not necessarily a death knell for drug sales, analysts say.

The label, second only to pulling the drug from the market, can impact sales but it depends on how badly the drug is needed, and this could be good news for Pfizer, analysts say.

The FDA said April 7 it was considering a black box label for Pfizer's blockbuster Celebrex, an arthritis painkiller with $3.3 billion in 2004 sales. On the same day, the agency asked Pfizer to withdraw its other arthritis drug, Bextra, which had $1.3 billion in 2004 sales. Just six months before, on Sept. 30, Merck withdrew Vioxx. All three of these drugs are in the same class of cox2 inhibitors and have been blamed for heart attacks and strokes.

"Definitely [Celebrex] sales are going to be impacted by the formalization of the black box," said Sena Lund, analyst for Cathay Financial. "Physicians do not ignore black box warnings because it becomes a matter of liability."

However, Lund said the loss of sales would be tempered by a lack of competition, with Celebrex's status as "the only cox2 in the market."

Andrew McDonald, research analyst for ThinkEquity Partners, said that black box warnings for many drugs "seriously impair drug sales," partly because physicians fear malpractice suits.

"Doctors, when they see a black box warning, it really makes them anxious in that they can imagine themselves, if an adverse event occurs, in a courtroom trying to explain to a judge why they prescribed the medicine when it says right on the label why it shouldn't be prescribed," said McDonald.

But the fear of liability is reduced in situations when the drug is the only treatment available. "If there aren't alternative therapies, then the drug will continue to do well in the marketplace," said McDonald.

The FDA, physicians and patients weigh benefits versus risks when making decisions about drugs, and when a drug offers a unique benefit, it gains an edge.

Cisapride, a treatment for severe nighttime heartburn, was given an black box warning by the FDA in 1995, and an expanded black box warning in 1998, because it was blamed for heart disorders resulting in deaths. Janssen Pharmaceutica withdrew it in 1999 after totaling $1 billion in sales for that year, said McDonald.

"This is a drug that, despite a warning, was still a phenomenal seller," said McDonald, referring to Cisapride.

A similar situation occurred when Remicade, a treatment for rheumatoid arthritis and Crohn's disease, received a black box warning. Remicade, a drug made by Centocor, can cause serious infections, according to the FDA. But McDonald said the drug is still a strong seller, totaling $2 billion in 2004 sales. (See correction.)

"In this case, the sales have not been terribly affected," said McDonald, referring to Remicade. "The needs for the drugs outweigh the risks associated with them. There's a similar story with Celebrex, in that there aren't very good alternatives."

Study: Celebrex As Risky As Vioxx

Fri, 15 Apr 2005 00:00:00 -0700

A study of New Zealand patients on two previously common arthritis drugs has found a similar risk of heart attacks and strokes regardless of the brand.

One of the drugs, Vioxx, was withdrawn late last year because of the cardiovascular risk but the other drug, Celebrex, is still sold.

The national medicines monitoring unit has analysed follow up information from 11,000 patients prescribed these drugs in 2001. Their findings are published in an international journal called Drug Safety.

Unit head Mira Harrison-Woolrych says the results show Celebrex is just as risky as Vioxx, despite quite a wide margin of error.

Health officials recently concluded the risks outweigh the benefits for all brands of these drugs and a decision on their future is due this month.

The pharmaceutical company Pfizer is challenging the study, saying four international studies found no increased cardiovascular risks from Celebrex.

"The FDA in the United States recently published a 'real life' observational study designed to assess the cardiovascular risk of all NSAIDS (including Celebrex and Vioxx) and found there was no increased risk associated with Celebrex, whereas there was a significantly increased risk associated with Vioxx use," says Pfizer Australia and New Zealand Medical Director, Bill Ketelbey.

It says the data in the New Zealand study lacks statistical power to detect differences between the medicines.

New Research On Arthritis Drug

Fri, 15 Apr 2005 00:00:00 -0700

Otago University has given health officials new information on an arthritis drug which is under threat of being withdrawn from the market.

Its Intensive Medicines Monitoring Programme has completed a study showing patients taking Celebrex have the same risk of heart attack or stroke as those taking the already withdrawn drug Vioxx.

Programme head Mira Harrison-Woolrych says they studied 11,000 people taking either of the drugs known as cox-2 inhibitors and found the same level of risk.

She says it is the first study of its kind, because it looks at the real-life use of the medicines as prescribed by New Zealand GPs.

However, drug company Pfizer claims the study should be read with extreme caution.

General manager Mark Crotty says it goes against a large body of evidence and a United States study of 1.3 million people found no increased risk with Celebrex.

He says the Otago study was a real life trial, not a clinical trial, and relied on vigilant reporting by GPs.

Health officials are due to decide this month whether all cox-2 inhibitors should be withdrawn.

Bextra Is Pulled Off Market

Fri, 08 Apr 2005 00:00:00 -0700

Tens of millions of users of Motrin, Aleve, Celebrex and other painkillers should be given more information about their risks, such as heart attacks or ulcers, the Food and Drug Administration said yesterday.

In a sweeping safety action, regulators in the United States and Europe also asked Pfizer Inc. to withdraw its prescription pain reliever Bextra, saying it could do more harm than good compared with other drugs.

The FDA's actions on both prescription and nonprescription drugs sent its strongest sign yet of a change in agency tone on safety. It began from a controversy over one drug, Vioxx, which Merck & Co. Inc. voluntarily withdrew in September.

The failure of Vioxx rattled the industry, raised questions about the FDA itself, and sent millions of patients scrambling for different medications.

That, in turn, led to safety questions about other drugs, some of which, such as ibuprofen, have been used for decades in a business worth hundreds of billions of dollars.

Bextra's withdrawal also could spawn a wave of product-liability cases involving the drug, long criticized by some health advocates.

"Finally, it's buried. And that's a good thing," said Eric Topol, a researcher at the Cleveland Clinic Foundation and a Vioxx critic.

"Today's actions protect and advance the health of the millions of Americans who rely on these drugs every day," Steven K. Galson, acting director of the FDA's Center for Drug Evaluation and Research, said in a statement.

The FDA lists nearly 50 drugs or drug combinations as "nonsteroidal anti-inflammatory drugs," or NSAIDs, including the prescription drugs Celebrex and Bextra.

The over-the-counter, or nonprescription, drugs include Motrin and Advil (both ibuprofens), Aleve (naproxen), Mobic and Diclofenac.

Excluded from the list are aspirin and acetaminophen, also known as Tylenol.

"The FDA is asking the manufacturers of all over-the-counter NSAIDs to revise their labels to include more specific information about the potential cardiovascular and gastrointestinal risks," the FDA statement said, adding that skin reactions were also a risk.

The FDA did not spell out the basis for its concerns about the drugs yesterday. It also was vague on the specific wording of the warnings, saying only that they would differ depending on whether the drug is sold by prescription or over the counter.

"We plan to develop our proposed text for the new labeling in the next few weeks, and will request that each sponsor adopt that text," said John Jenkins, an official in the FDA's Office of New Drugs.

Some experts, while expressing skepticism about the impact of labels, praised the FDA's new stance on drug safety.

"It may be helpful if it gets people's attention not to exceed the over-the-counter dose," said Alastair J.J. Wood, a professor at Vanderbilt University Medical School and chairman of the FDA's arthritis panel.

Reaction was mixed among customers at a CVS store on Chestnut Street in Center City.

"I would still take them, even with a warning," said Linda Tripp, 59, of West Philadelphia, who said she used Advil for knee pain. "They have given me two and a half to three hours of slow relief."

But Tanya Thompson, 52, of North Philadelphia, said she read the labels and tried to heed them. "Let them put warnings on everything," Thompson said. "It's up to the consumer to decide whether to use it."

The FDA took the action almost seven weeks after its own panel of advisers recommended that the prescription drugs Bextra, Celebrex and Vioxx all known as Cox-2 inhibitors were safe enough to remain on the market.

However, the panel's vote had been close on Bextra and Vioxx, leading to speculation that the FDA might rule against them.

"This didn't surprise me a bit, and I'm a bit relieved," said Wood, who had voted against letting Bextra stay on, and Vioxx return to, the market.

All three drugs were designed to relieve pain without the older drugs' risks of gastrointestinal side effects, such as ulcers and internal bleeding. However, studies have found that the newer drugs carry higher risk of heart attack or strokes, or kidney and skin problems.

The FDA said it had asked Pfizer on Wednesday evening to cease selling Bextra after it concluded that the drug's risk of heart and skin reactions exceeded its benefits compared with other drugs on the market.

"Patients currently taking Bextra should contact their physicians to consider alternative treatments," the FDA said in a statement yesterday.

Hours later, European regulators contacted Pfizer and asked it to suspend sales of Bextra in the 25-nation European Union, according to Pfizer. It was unclear whether the FDA and European Union had coordinated their actions.

In its statement, Pfizer disputed the regulators' logic but said that, "in deference to the agency's views, the company has agreed to suspend sales of the medicine pending further discussions with the FDA."

Bextra was Pfizer's seventh-best-selling drug last year, with sales of $1.24 billion, but its sales have fallen.

The FDA let Pfizer keep Celebrex on the market but asked it to include more safety data about heart and stroke risks and insert a detailed Medication Guide for physicians.

Pfizer readily agreed and said it would "add expanded risk information."

Celebrex was Pfizer's No. 3-selling drug, with $2.78 billion in sales last year. But despite Pfizer's efforts to shield it from Vioxx-related fears, Celebrex sales have plunged.

Sidney M. Wolfe, director of health research at the advocacy group Public Citizen, faulted the FDA for not going far enough. "While we are pleased that the FDA has taken Bextra off the market, it has recklessly allowed Celebrex to continue to be sold."

Consumers Union also called for more action. "Removal of a dangerous drug from the market is a good thing, but it leads to the larger question: Why were these unsafe drugs being sold in the first place?" said Jeannine Kenney, senior policy analyst. "The FDA badly needs reform of its reactive, passive drug-safety system."

The FDA said no decision had been made yet on relaunching Vioxx, an option Merck raised during the advisory meeting. The agency said it would "carefully review" any new Merck application.

Merck said in its statement that it "respects the FDA decision" on Bextra and "looks forward to discussions with the FDA."

"Clearly, they want to take a second look, very careful look," at Vioxx before letting it back on the market, said Louis Morris, a former FDA official and now an industry consultant, who also was on the FDA panel.

Several experts said the Bextra withdrawal boded ill for Vioxx's return. "The hurdles are so high now. There's no chance," Wood said.

Bextra Taken Off Market After FDA Warns of Risks

Fri, 08 Apr 2005 00:00:00 -0700

Pfizer Inc. reluctantly halted sales of its arthritis painkiller Bextra on Thursday after the Food and Drug Administration concluded that it posed too many serious safety risks. It was the second major arthritis medication to be withdrawn in the last six months.

In addition to asking Pfizer to stop selling its $1.4 billion-a-year blockbuster, the FDA concluded that the entire class of anti-inflammatory painkillers carries a potentially increased risk of heart attack and stroke and it told manufacturers to substantially toughen the safety warnings on almost all nonnarcotic painkillers still on the market.

Prescription painkillers such as Celebrex and Mobic will remain available, but with the strongest safety warnings the FDA can require. The makers of nonprescription pain relievers such as Motrin and Aleve will be required to tell consumers more about their risks warning them to take the pills only for the short periods recommended on the labels, usually no more than two weeks.

For millions of pain sufferers, especially people with chronic arthritis, the FDA action was the latest twist in six months of misfortune that began with Merck & Co.'s withdrawal of the popular painkiller Vioxx. Drugs such as Vioxx, Celebrex and Bextra, hailed not long ago as near-miracle therapies, are now either gone or under a cloud, along with dozens of other anti-inflammatory drugs.

"Today's actions protect and advance the health of the millions of Americans who rely on these drugs every day," Steven Galson, acting director of FDA's Center for Drug Evaluation and Research, said in a statement. "FDA is providing the public information based on the latest available scientific data to guide the careful and appropriate use of these drugs."

Thursday's actions were among the most sweeping ever initiated by the FDA, which has traditionally been reluctant to take drugs off the market and cautious about branding an entire class of drugs as worrisome.

The FDA went beyond the recommendations of a 32-member panel of expert advisers that it brought together in February for a three-day public hearing about all nonnarcotic painkillers. That panel narrowly recommended that Bextra should be allowed to remain available and that Vioxx should be allowed back on the market under certain conditions. Galson said that because the expert panel's votes were so close, the agency believed that its actions are consistent with the recommendations.

Alastair Wood of Vanderbilt University, chairman of that committee, applauded the FDA Thursday for "asserting itself and taking a strong stand."

"When a bare minority votes to keep a drug on the market, that's not a safety endorsement - it's a devastating indictment," Wood said. "The FDA saw that and responded."

By taking Bextra off the market and requiring serious warnings on all other medications in the class known as non-steroidal anti-inflammatory drugs, or NSAIDs, the agency will significantly affect the lives of tens of millions of patients in pain who use them.

Bextra: More Risks Than Benefits

Fri, 08 Apr 2005 00:00:00 -0700

The Food and Drug Administration has asked pharmaceutical company Pfizer to pull Bextra off the market because of evidence that it increases the risk of heart attacks, strokes and a potentially fatal skin condition as well.

The Early Show medical correspondent Dr. Emily Senay explains what this might mean to you.

Bextra falls into a class of painkillers known as Cox-2 inhibtors that are very popular among people with arthritis. They have been in the news a lot lately (since the fall, in fact) when one of them, Vioxx, was voluntarily pulled of the market because people who took it were found to be at an increased risk of heart attack and stroke.

The FDA now says that Bextra poses these same heart risks and, in addition, people taking the drug are at risk for a serious and sometimes fatal skin reaction.

So what should patients taking Bextra do?

Pfizer, which makes Bextra, suggests that anybody on the drug stop taking it and contact their physician about other treatment options.

The FDA now wants all the drugs in this class that are still on the market to carry what's known as a "black box warning," which states clearly that these Cox-2 inhibitors can increase your chances of cardiovascular problems.

Merck, which manufactures Vioxx, stands by the decision to voluntarily remove the drug from the market. However, the company maintains that Vioxx offers unique benefits among the Cox-2 class of drugs.

So how is it that Celebrex (another very popular Cox-2) is still on the market? In February, a panel that advises the FDA said that Celebrex seemed to have the fewest cardiovascular side effects of all the Cox-2 drugs. But, as mentioned earlier, the government now wants it to carry one of those black box warning labels.

Over-the counter pain relievers such as Advil and Aleve, still very popular with arthritis sufferers, are not Cox-2 inhibitors. But the FDA has asked the makers of these medications to revise their labels to say that people who take them are at an increased risk for heart attacks, stroke, gastrointestinal bleeding and serious skin reactions.

The FDA says the the warning labels which will be placed on the over-the counter pain relievers will not be placed on aspirin because it has "special benefits when taken in low doses."

Another Drug For Pain Off Market

Fri, 08 Apr 2005 00:00:00 -0700

The Food and Drug Administration announced Thursday that Pfizer has agreed to stop selling Bextra, a popular arthritis drug, because its risks outweigh its benefits.

The FDA also will now require a "black box" warning the strongest warning on the labels of Pfizer's blockbuster arthritis drug, Celebrex, and other, older prescription anti-inflammatory pain relievers such as ibuprofen and naproxen. The warning will highlight the drugs' risks of heart attacks, strokes and bleeding of the digestive tract.

Over-the-counter anti-inflammatory pain relievers will have to add similar information to their labels, as well as a warning about rare, potentially fatal skin reactions, which the prescription drugs' labels already carry.

The halting of Bextra sales is just the latest blow to COX-2 inhibitor drugs. A decade ago, the drugs were touted as "super aspirins" because it was thought they could relieve pain and inflammation while unlike aspirin leaving the stomach lining intact.

Of all the anti-inflammatory pain-relievers, Bextra has been the one most commonly cited in reports of severe skin reactions, Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research, said at a news conference.

The FDA asked Pfizer to stop selling Bextra because "it had no unique benefit, and it had the unique risk: the skin reaction," John Jenkins, director of the FDA's Office of New Drugs, said during the briefing. Galson said Celebrex is still on the market because the drug has a "positive risk/benefit balance."

At the request of European regulators, Pfizer said, it is also suspending sales of Bextra in the European Union. About 7 million people worldwide have taken Bextra since it was launched in 2001, Pfizer spokeswoman Susan Bro said. And 28 million worldwide have taken Celebrex since its launch in 2000, Bro said.

Since concerns over cardiovascular safety spurred Merck to pull its arthritis drug Vioxx off the market Sept. 30, "the FDA has been engaged in a re-evaluation of this class of drugs," Galson said.

In February, an FDA advisory panel unanimously concluded that Bextra, Vioxx and Celebrex, all COX-2 inhibitors, significantly raise heart and stroke risk. Nonetheless, a majority voted for keeping them on the market with restrictions. With Celebrex, the vote was 31-1 in favor of continued sales. But the panelists were nearly evenly split on whether Bextra or Vioxx should be on the market.

"Pfizer respectfully disagrees with FDA's position regarding the overall risk/benefit profile of Bextra," the company said in a statement. "For now, patients should stop taking Bextra and contact their physicians about appropriate treatment options." Pfizer said it would discuss with the FDA how the company might resume selling Bextra.

Curt Furberg, who voted against Bextra and Vioxx at the February meeting, called the FDA's announcement about Bextra "a victory for public health."

"I did not expect them to have the guts to do it," said Furberg, a medical epidemiologist at the Wake Forest University School of Medicine in North Carolina. "I feel vindicated."

Bextra Ban a Good Step, But FDA Should Pull Celebrex Too

Thu, 07 Apr 2005 00:00:00 -0700

In January, Public Citizen petitioned to have Bextra and Celebrex, two COX-2 inhibitors, removed from the market because they increase the risk of heart attacks. Today, the U.S. Food and Drug Administration (FDA) has called on Pfizer to pull Bextra from the shelves and place a warning on Celebrex.

While we are pleased that the FDA has taken Bextra off the market, it has recklessly allowed Celebrex to continue to be sold. An unpublished study finished in 2000 indicated increased cardiac risks associated with Celebrex.

Last year, almost twice as many prescriptions were written for Celebrex as for Bextra, 23.9 million prescriptions compared to 12.9 million. Neither Bextra nor Celebrex protects the gastrointestinal tract as drugmakers claim. Given that neither drug has any unique benefits but both carry unique cardiac risks, it is unconscionable to leave Celebrex on the market.

In addition, the FDA is sowing dangerous confusion by requiring all nonsteroidal anti-inflammatory drugs (NSAIDs) Celebrex and all non-aspirin NSAIDs to warn about increased cardiac risks, even though the risks of Celebrex are clearly higher than at least one NSAID, naproxen.

The FDA said today that it took its actions "based on the available scientific data, including data accumulated since the drugs were approved." But the agencys job is to ensure that drugs with risks that outweigh the benefits are taken off the market. We call on Congress, which is finally delving into FDAs operations, to investigate why the agency is not also pulling the equally dangerous Celebrex from the shelves.

Note: Bextra is the tenth prescription drug to be taken off the market in the past seven years that Public Citizen had previously warned consumers not to use. For four of the drugs: Vioxx, Baycol, Rezulin and Serzone; Public Citizen issued warnings more than two years before their removal from the market. In April 2001, Public Citizen warned patients not to use Celebrex

Health Canada Has Asked Pfizer to Suspend Sales of Its Drug Bextra and Informs Canadians of New Restrictions On The Use of Celebrex

Thu, 07 Apr 2005 00:00:00 -0700

Health Canada has asked Pfizer Canada to voluntarily discontinue sales of its drug Bextra in Canada until safety issues have been resolved. Pfizer has agreed and will be discontinuing sales.

Health Canada has asked the manufacturer to submit evidence to establish the safety of this drug product under the conditions of use for which it is recommended. In addition the manufacturer has been asked to provide Health Canada with a risk/benefit analysis indicating the product's unique therapeutic advantage.

Health Canada's decision is based on an ongoing review of information with regard to serious, potentially life-threatening skin reactions. It is based on Canadian and foreign data, including publicly available information from the United States. Health Canada has already published, on December 10, 2004 a public advisory indicating that serious potentially life threatening skin reactions had been reported in patients taking Bextra. The prescribing information and patient instructions were modified at that time to reflect the higher incidence of these events.

We encourage people taking Bextra to contact their physician to discuss discontinuing use and alternative treatments. After having consulted with a physician, consumers should return the product to their pharmacy. In order to avoid contaminating ground or municipal water systems, the product should not be flushed down the toilet or sink.

In addition to this action on Bextra Health Canada is also recommending important new usage restrictions for Celebrex(celecoxib), another selective COX-2 inhibitor.

The usage restrictions on Celebrex are based on Health Canada's ongoing scientific review of the cardiovascular safety of selective COX-2 inhibitor non-steroidal anti-inflammatory drugs (NSAIDs). Products such as Celebrex and Bextra work by selectively blocking an enzyme commonly known as COX-2 that is linked to pain, inflammation and fever.

Health Canada's ongoing scientific review started in the fall of 2004, when the long-term use of a similar drug, Vioxx(rofecoxib), was linked to an increased risk of heart attack and stroke, and its manufacturer withdrew it from the global market.

New restrictions concerning the use of Celebrex are as follows:

Patients who have had a heart attack or stroke, experienced serious chest pain related to heart disease, or who have had serious diseases of the heart such as congestive heart failure, should NOT use this medication.

Patients who have significant risk factors for heart attack or stroke should be aware that using this drug may increase this risk. Risk factors for heart attack and stroke include high blood pressure (treated or untreated), high cholesterol, diabetes and smoking. In consultation with their doctors, patients with such risk factors should consider using other types of medications or pain relief therapies.

This medication should be prescribed and used at the lowest possible dose, and for the shortest, necessary period of time.

Selective COX-2 inhibitor NSAIDs should only be used to treat the pain and inflammation of arthritis, and certain types of acute pain. These drugs may be used to treat osteoarthritis and rheumatoid arthritis. Celebrex may be used for the short-term (one week or less) management of moderate to severe pain in adults caused by conditions such as sprains, surgery or tooth extractions. In the past, Celebrex had been used to treat family polyposis (the presence of multiple polyps in the colon) but this indication was cancelled in December, 2004 and a public advisory was issued at that time.

Health Canada scientists continue to review Canadian and international safety data and other sources of information regarding cardiovascular risk and the use of other COX-2 inhibitor NSAIDs. They are also consulting external experts in fields such as cardiology, rheumatology and pharmacology. Health Canada will advise Canadians if other safety concerns arise.

Health Canada urges patients using Celebrex to consult their physicians in order to weigh the risks and benefits of these drugs in light of their own medical circumstances.

Pfizer Takes Painkiller Bextra Off Market

Thu, 07 Apr 2005 00:00:00 -0700

The painkiller Bextra was taken off the market Thursday, and the government wants similar prescription drugs to carry the strongest possible warnings about increased risk of heart attack and stroke among the millions of people who rely on them.

Pfizer Inc. suspended sales of Bextra in the United States and the European Union at the request of the Food and Drug Administration and European regulators. The company said that the FDA, in seeking Bextra's withdrawal, cited a risk of serious, sometimes fatal, skin reactions to Bextra on top of the risks shared by other similar drugs.

At issue are a broad class of painkillers known as nonsteroidal anti-inflammatory drugs, or NSAIDS. Bextra is a particular type of NSAID known as a Cox-2 inhibitor, a class of blockbuster sellers particularly popular among arthritis sufferers until a competitor Vioxx was pulled off the market last fall. That sparked questions about the safety of all similar drugs.

Pfizer's Celebrex can still sell, the FDA announced Thursday. But it, and all other prescription NSAIDS, must carry a black-box warning on its label that users may face an increased risk of cardiovascular side effects.

Scientists don't have enough information yet to tell if one of the remaining prescription painkillers is safer than another, FDA officials stressed. But, the agency decided that Bextra was more dangerous than its competitors because of the added skin side effect.

In addition to the prescription drugs, the FDA asked manufacturers of over-the-counter NSAID painkillers to revise their labels to clarify information about the risks of cardiovascular incidents, gastrointestinal bleeding and rare but serious skin reactions.

That doesn't mean the nonprescription drugs are dangerous, FDA officials stressed but the strengthened wording will make clear that patients should take those drugs only at the labeled dosage for short periods of time.

"People should not have a concern about continuing to take those products per those directions," said Dr. Steven Galson, acting director of FDA's Center for Drug Evaluation and Research.

For users of prescription-strength NSAIDS, the government said there was no reason to panic but that people should consult their physicians about which painkiller is best suited for them and to take the lowest effective dose.

"All these risks we're talking about have already been known," Galson stressed. "People should not worry about, from today to tomorrow, stopping the products."

Pfizer's advice to Bextra users: "For now, patients should stop taking Bextra and contact their physicians about appropriate treatment options."

Pfizer said it "respectfully disagrees" with FDA that Bextra was too risky to continue selling, and pledged further discussions with the agency about the possibility of returning it to the market.

Pfizer shares fell about 3 percent soon after Thursday's opening bell on the New York Stock Exchange.

In February, advisers to the FDA had recommended that people who depend on Celebrex, Bextra and Vioxx be allowed to continue to use them despite the health risks although it only narrowly backed Bextra. The panel said Vioxx posed the greatest heart risk and that Celebrex seemed have the fewest cardiovascular side effects among the Cox-2 drugs. It also recommended that the prescription drugs carry strong warnings, and that more study be done to better understand the drugs' risks.

Pfizer Halts Sales of Bextra

Thu, 07 Apr 2005 00:00:00 -0700

Pfizer has agreed to stop selling Bextra, a popular arthritis drug, the Food and Drug Administration announced Thursday, because the FDA believes its risks outweigh its benefits.

The FDA will also now require a black box warning the strongest type of warning on the labels of Pfizer's blockbuster arthritis drug, Celebrex, and other, older prescription anti-inflammatory pain-relievers, such as ibuprofen and naproxen. The warning will highlight the drugs' risks of heart attacks, strokes and digestive tract bleeding.

Over-the-counter pain relievers will have to add similar information to their labels, as well as a warning about rare, but potentially fatal skin reactions, which already is on the prescription drug labels.

The halting of Bextra sales is just the latest blow to COX-2 inhibitor drugs. A decade ago, COX-2 inhibitors had been touted as "super aspirins" because it was thought they could relieve pain and inflammation like aspirin while, unlike that drug, leaving the stomach intact.

Since cardiovascular safety concerns spurred Merck (MRK) to pull its blockbuster arthritis drug Vioxx off the market Sept. 30, "the FDA has been engaged in a re-evaluation of this class of drugs," Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research, said at a press conference.

That process culminated in February with a three-day joint meeting of two FDA advisory committees, Galson said. Although panel members unanimously concluded that Bextra, Vioxx and Celebrex, all so-called COX-2 inhibitor drugs, significantly raise heart and stroke risk, a majority voted for keeping them on the market with restrictions to limit their use.

With Celebrex, the vote was 31-1 in favor of continued sales. But the panelists were nearly evenly split on whether Bextra or Vioxx should be on the market.

"Pfizer respectfully disagrees with FDA's position regarding the overall risk/benefit profile of Bextra," the company said in a statement. "For now, patients should stop taking Bextra and contact their physicians about appropriate treatment options."

In its statement, Pfizer said it would discuss with the FDA how the company might resume "making Bextra available to physicians and patients." The drug was approved by the FDA in November 2001.

It's not clear how suspension of Bextra sales might affect Vioxx's future. Merck executive Peter Kim surprised many at the advisory panel meeting when he suggested that Merck might resume marketing Vioxx if the advisory committee and the FDA conclude that the benefits of COX-2 inhibitors outweigh their risks.

"Merck respects the FDA's decision" on COX-2 inhibitors, the company said Thursday in a statement. "We look forward to discussions with the FDA."

Curt Furberg, who voted against Bextra and Vioxx at the February meeting and has published research about Bextra's cardiovascular risks, called FDA's announcement about Bextra "a victory for public health."

"I did not expect them to have the guts to do it," said Furberg, a medical epidemiologist at the Wake Forest University School of Medicine in Winston-Salem, N.C. "I feel vindicated."

Bextra Pulled Off Shelves

Thu, 07 Apr 2005 00:00:00 -0700

PHILLIPS: Well, important medical news to tell you about now. The drugmaker Pfizer is pulling its popular arthritis painkiller Bextra off the market.

The move comes at the urging of the Food and Drug Administration, which is also recommending the strongest possible safety warning for Pfizer's other arthritis drug, Celebrex.

CNN medical correspondent Elizabeth Cohen here to talk about what she knows about these drugs and the fact that Bextra is being pulled off the shelf.

ELIZABETH COHEN, CNN MEDICAL CORRESPONDENT: That's right.

And this is sort of yet another painkiller that's gotten into trouble. Now, I'll read you what officially what the FDA said today. They said, the FDA has asked Pfizer to withdraw Bextra from the market because the overall risk-vs.-benefit profile for the drug is unfavorable. That is a fancy way of saying that it does more harm than good.

Specifically, the harm is the studies found that people taking Bextra were more likely to have a heart attack or stroke than those who didn't, also more likely to contract a potentially deadly skin disease. And so the FDA decided to ask Pfizer. Pfizer said that they disagreed with the FDA's analysis, but that they agreed they would take it off the market.

Now, this is a very popular drug. In fact, last year, there were 12.8 prescriptions written for Bextra. And that meant $1.2 billion in sales. So, what do you do if you're taking Bextra? I'm sure you're asking yourself, what do I do? And Pfizer says stop taking it and talk to your doctor about alternatives.

But, remember, including over-the-counter painkillers, also carry risks. Now, it's important to note that some people, in consultation with their doctors, will decide that they want to continue taking drugs like Celebrex, which now has to carry a big warning about cardiovascular risks, and will want to continue to take over-the- counter drugs, despite the FDA's warning about heart and stroke risks.

And, Kyra, the reason for that is that some people are in so much pain that they have trouble going about their day. And they and their doctors may say, you know what? I'm not at a very particularly high risk of having a heart attack or stroke. So, if it elevates my risk a little bit, that's OK, because these drugs help me make it through the day. Other people are going to make different situations. It's very individual.

PHILLIPS: Well, we see that a lot of people take Bextra or took Bextra. But I bet even more take over-the-counter painkillers. So, is it still OK to take other how do you know what's OK to take now and what's not?

COHEN: It's so confusing.

PHILLIPS: Yes.

COHEN: It's so confusing. We're going to give people a little advice here. What the Food and Drug Administration has to say about over-the-counter painkillers like Advil, Motrin, Aleve, that class of nonsteroidal anti-inflammatories is, only take the dose that is recommended on the label. Take these drugs for no longer than two weeks.

And, after two weeks, see your doctor. When people really ran into trouble with these drugs, for the most part, it was when they were taking dosages that were too high and when they were taking them for month after month or even year after year after year.

PHILLIPS: All right, Bextra is getting pulled, but Celebrex is saying, but Celebrex having to have this massive warning label now. Why not just pull that one also?

PHILLIPS: Right. It's called a black box warning. And the reason why it's called that is that it's in a big black box at the top of the label. So, it's very clear, cardiovascular risk, so that you know the risk you're taking.

We asked the FDA, why are you letting Celebrex stay on the market? And they said because this deadly skin disease seems to be more likely when you take Bextra. And they said, in fact, as of December, that four people had died when they were taking Bextra from this skin disorder. So, it was really the skin disorder being associated with Bextra. That's what really tipped the scales for the FDA.

Pfizer Pulls Bextra

Thu, 07 Apr 2005 00:00:00 -0700

First, though, there is important medical news that you need to know about. The drugmaker Pfizer is pulling its arthritis painkiller Bextra off the market. The Food and Drug Administration asked for the recall. The FDA also called for the strongest possible warning on Pfizer's other big arthritis painkiller, Celebrex.

Our medical correspondent Elizabeth Cohen standing by with important details.

Elizabeth, what's going on?

ELIZABETH COHEN, CNN MEDICAL CORRESPONDENT: Wolf, well the Food and Drug Administration has just had a press conference, and issued this statement. And in it they say the FDA has asked Pfizer to withdraw Bextra from the market because the overall risk versus the benefit profile for the drug is unfavorable.

Well, that's a fancy way of saying that when they looked at the data, Bextra did more harm than good. And the harm, specifically, is an increased risk of having a heart attack or stroke while taking Bextra, and also an increased risk of having a potentially life-threatening skin condition.

So, now, of course, the big question for Bextra users is, what do I do? Well, Pfizer says stop taking Bextra. Stop taking it and talk to your doctor, those are the instructions from Pfizer. And they also say, when you talk to your doctor about alternatives, remember that other painkillers also carry risks.

Wolf, you mentioned Celebrex, and the FDA has said that Celebrex now needs to carry it's called a black box warning. That's a warning in a big prominent black box that talks about the heart attack and stroke risk and also the increased risk of having gastrointestinal bleeding.

The sales for Bextra have been very high, of course won't be high much longer. 12.8 million prescriptions for Bextra were written in 2004. $1.2 billion in sales.

Now, Wolf, another thing that people need to remember is, if they're take Celebrex, or even if they're taking over-the-counter painkillers, which also carries some increased risk, for some people those risks are worth it. Some people are going to say, "My pain is so bad I can't really live my life the way I want to." And they and their doctor together might decide that it's worth them continuing to take these drugs Wolf.

BLITZER: What about the people who would take these painkillers, especially the over-the-counter painkillers? What are they supposed to do now?

COHEN: Right. Well, they also should talk to their doctor, and the should follow the Food and Drug Administration's advice. And that advice specifically is to take the dose that's recommend on the label. Take it for no longer than two weeks. If you want to take it for longer than two weeks, you need to talk to your doctor.

Wolf, the problems that the FDA found when people were taking over-the-counter drugs like Advil or Alleve, they tended to be when people took them for a long time and at high doses.

BLITZER: The FDA asked for Bextra to come off the market, but Celebrex still staying on the market. Why?

COHEN: What tipped the scales apparently, according to the FDA, is that Bextra seemed to have a more severe relationship with this life-threatening skin condition. In fact, in December, they said that four people had died because of this skin condition when they were taking Bextra.

So it was the skin condition, not the heart attack and stroke risk. The heart attack and stroke risk seems to be the same with Celebrex and Bexra, but the skin condition seems to be worse for people taking Bextra.

BLITZER: Elizabeth Cohen reporting for us important information, medical information. Thanks, Elizabeth, very much.

FDA Pulls Painkiller, Orders New Warnings on Others

Thu, 07 Apr 2005 00:00:00 -0700

In a sweeping move to address one of its worst drug safety debacles, the Food and Drug Administration announced Thursday that dozens of widely used prescription painkillers must now carry the government's strongest warning that they pose risks of heart attacks and strokes.

And one blockbuster painkiller, Bextra, was removed from the market. The FDA said it can cause potentially life-threatening skin reactions in some patients, as well as heart problems.

Bextra, along with Celebrex, have been medications of choice for millions of patients suffering from arthritis and other forms of chronic pain. The two drugs, known as COX-2 inhibitors, belong to a much larger category of medications called nonsteroidal anti-inflammatory drugs, or NSAIDs.

All prescription drugs classified as NSAIDs must now carry the stronger warning label.

In weaker, nonprescription forms such as Advil, Motrin and Aleve, NSAIDs are likely to be found in almost every household in America. The FDA emphasized that these nonprescription versions are safe. But it said they should be taken according to directions and only for limited periods of time.

In other action, the agency made it less likely that another COX-2 inhibitor taken off the market last fall Vioxx will become available again. The FDA said its maker, Merck, must submit a new application for approval and go before an expert advisory panel. It was Merck's decision to withdraw Vioxx that marked the beginning of cascading concerns about the painkillers.

The FDA's actions Thursday, which go beyond the steps proposed in February by its scientific advisory committee, suggest the embattled agency has decided to take a tougher approach to the problem of health risks that surface in drugs after they have been approved for market.

Thursday's action was one of the largest relabeling orders in FDA history.

In recent months, critics in Congress and elsewhere have subjected the agency to criticism for relying too much on drug makers to sound the alarm over potential safety threats that surface after drugs have reached the market and begun to be used by patients.

And the actions were at least partial vindication for agency whistle-blower Dr. David Graham, who had unsuccessfully tried last year to warn of problems with Vioxx. Graham testified in congressional hearings that Bextra should also be withdrawn from the market.

Graham has estimated that of the millions who took Vioxx for arthritis, back pain and other ailments, as many 139,000 Americans may have suffered heart attacks and strokes. Of those, 26,000 to 55,600 may have died, he suggested. The FDA disputes Graham's calculations and says the total number of fatalities is probably significantly lower, but it does not dispute the seriousness of the problem.

Signaling a more aggressive strategy, Dr. Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research, said the public can expect further regulatory decisions and information alerts about the risks and benefits of painkillers.

"Let me emphasize now, this announcement is unlikely to be the last word you'll hear on these drugs," Galson told reporters on a conference call. "Clinical investigations continue. And in our new spirit of keeping the public informed earlier of emerging drug safety issues we may be providing further modifications as new information comes to light."

He said the FDA concluded that all prescription NSAID drugs, at least in theory, can increase the risk of heart attacks and strokes.

The tougher approach is in line with demands by congressional and other critics that the FDA become more aggressive in monitoring drugs it has approved for market.

"The FDA took a stand in support of public health," said Dr. Curt Furberg of Wake Forest University, who had criticized the agency's handling of safety concerns about Vioxx. "I think patients now can have some hope that the FDA in the future will be the guardian of drug safety."

Other experts suggested the agency's action could lead to confusion for patients and doctors, particularly since there is a dearth of hard data on the heart risks of most of the nonsteroidal anti-inflammatory drugs. For example, there is no way at present to know whether some of the drugs are safer than others.

"I am having a very difficult time managing my post-surgery patients," said Dr. Richard Vanis, an orthopedic surgeon in Arcadia, Calif. Vanis said he has been prescribing narcotic pain relievers for high-risk patients who would have been given Vioxx in the past. Some of the drugs are "horribly addicting," he said.

On Thursday, Vanis examined a 61-year-old patient with severe arthritis and heart disease who had run out of Vioxx. The patient refused to stop taking the pain reliever when it was recalled last fall.

"I don't know what I am going to do in his case," Vanis said.

The FDA said all prescription-strength forms of NSAIDS would now carry a so-called "black-box" warning, the strongest it can impose. The warnings will be printed in bold type and surrounded by a black box at the top of instructions provided to doctors.

Lower-strength over-the-counter versions of the traditional drugs will not carry such a dramatic warning, though patient information will be changed to include details about possible heart and stroke risks.

The FDA sought to reassure patients taking nonprescription painkillers that they face no excessive risks. "The over-the-counter products, when taken according to directions are not an issue, and people should not be concerned," the FDA's Galson said.

He also stressed that patients taking aspirin to reduce their risk of having a heart attack should continue to do so. "None of this applies to aspirin," Galson said. "It has special benefits when taken in low doses."

The FDA actions were a blow to Pfizer Inc., which makes Bextra and Celebrex, a far more popular prescription drug in the COX-2 family. Touted as a stomach-friendly alternative to aspirin and other drugs, COX-2 inhibitors were heavily advertised by drug companies.

Pfizer said it disagreed with the FDA's decision to withdraw the drug, but had deferred to the wishes of regulators. The company also agreed to conduct additional long-term studies of the benefits and risks of Celebrex.

More than 500 cases are pending against Merck from patients who claim they were harmed by Vioxx.

A congressional investigation last year revealed that the FDA had downplayed or ignored repeated warnings from its own drug safety reviewers and from academic scientists about the cardiovascular risks of Vioxx. That led lawmakers to call for the creation of a much stronger and more independent drug safety office within the agency.

The stronger warning label on Celebrex is expected to have the effect of sharply restricting its use. As for Vioxx, Dr. Alastair J.J. Wood of Vanderbilt University Medical Center, said, "It seems inconceivable to me that Merck would try to bring it back."

Wood chaired an expert advisory panel that met for three days earlier this year to hear testimony and weigh the risks and benefits of COX-2 drugs. The panel recommended that Vioxx, Celebrex and Bextra should be available on the market, albeit with black box warnings. Those recommendations led Merck to indicate it might try to bring Vioxx back.

That possibility dimmed as a result of Thursday's announcements, Wood was suggesting.

Graham, the FDA whistle-blower, said in an interview he was glad the FDA finally agreed with him. But he said the agency's warning on Celebrex did not go far enough.

"I'm disappointed they didn't ban the (high) 400-milligram dose of Celebrex," Graham said. "The benefit of the higher dose doesn't exceed the risk, and I would challenge the FDA to present evidence to the contrary."

Agency officials said they are urging patients on Celebrex to take the smallest possible dose for the shortest possible time.

The consumer advocacy group Public Citizen said the FDA should have taken Celebrex off the market as well.

Meantime, a study published in the Journal of Immunology found that COX-2 drugs may have other powerful side effects. Laboratory and animal tests showed the drugs may also suppress the immune system by affecting antibodies that attack invading germs.

How Merck Stacked the Vioxx Deck

Thu, 31 Mar 2005 00:00:00 -0800

The same week that drug manufacturer Merck pulled its highly profitable painkiller, Vioxx, from the market last September, acknowledging that it was linked to heart attacks and strokes, a Las Vegas legend dropped into our local poker game. Ray is one of poker's few long-term success stories. A math wiz, highly praised author of several authoritative books on game theory and high-limit poker, and a practicing Buddhist, Ray was reminiscing about his early days in Las Vegas.

"Cheating was rampant," he said. "Stripped decks, wired hands, coolers, seconds, holdouts and marked cards. You name it, they did it the dealers and the players."

Ray had been able to make a great living in poker because he assumed the games might be rigged and acted accordingly. He studied the players and dealers, even watched videos of how card dealers dealt off the bottom of the deck or from the middle. He always expected the worst and was prepared.

"You weren't bothered playing with a bunch of crooks?" I asked.

Ray laughed. "You got to play with someone. We all have cheat in us, given the right circumstances." He smiled slyly. "But even cheats don't cheat all the time. The trick is to know when and how."

With its spectacular medical advances, Big Pharma is the only game in town. We cannot walk away; we must play. But unlike Ray, we are reluctant to assume that drug companies are rigging the outcome. Without this requisite skepticism, we are at their mercy in this case, with fatal consequences. The U.S. Food and Drug Administration has linked Vioxx, since it was released in 1999, to more than 27,000 acute heart attacks and sudden cardiac deaths. What the agency didn't report was its own culpability in the debacle.

Even the disclosure of tragic deaths, though, won't stop the same malfeasance from happening again. In order to protect ourselves as patients, we need to know how the game might be fixed. Dissecting the way that Merck developed Vioxx gives us a perfect opportunity.

I was initially reluctant to write another piece on the Vioxx scandal. The mainstream press has more than adequately pointed the finger of blame at Merck for knowing the cardiovascular risks of Vioxx and yet minimizing them to reap huge economic rewards. The medical literature has been equally damning. Two months after Vioxx was recalled, Dr. Richard Horton, editor in chief of the British medical journal Lancet, wrote: "With Vioxx, Merck and the F.D.A. acted out of ruthless, short-sighted, and irresponsible self-interest."

But the medical literature related to Vioxx suggests an even more onerous possibility, which is that Merck intentionally designed its studies to avoid discovering the truth about the potential C.V. risks of Vioxx. I have not been privy to the company's private staff meetings and internal documents. But it has been my experience that undertaking any major research study involves extensive consultation between experts in all pertinent fields, including pharmacologists, epidemiologists, statisticians and business managers. Given the enormous intellectual investment in the design of a drug like Vioxx, it is reasonable to presume that all potential outcomes were seriously entertained. I must presume that Merck would factor in what might happen to Vioxx sales with each study result. And so it's hard to escape the sadly cynical conclusion that the company consciously crafted its tests to avoid exposing the risks of Vioxx to the public.

After all, the stakes of new drug development are enormous. Only a fraction of new drugs submitted to the FDA for approval make it to market; the average cost per approved drug is over $800 million. Any drug that makes it into the marketplace is a potential bonanza to be coddled, cherished and protected. A drug patent lasts 17 years, and then the drug is thrown to the generic manufacturers. The FDA approved Vioxx for sale in May 1999. By 2004, 20 million Americans had taken the painkiller and its annual sales exceeded $2.5 billion. Is it any wonder that Merck sought to present Vioxx to the public in the best possible light?

To understand Merck's approach, we need a crash course in biology. COX (cyclooxygenase) is an enzyme in the body that produces an inflammatory response swelling, fever and pain. Drugs that reduce COX activity are called NSAIDs, and traditionally include aspirin and ibuprofen. But COX is present throughout the body and has a host of other effects, some of which are beneficial. For example, it helps protect the lining of the G.I. (gastrointestinal) tract from ulceration and bleeding.

Approximately 1 in 1,200 patients taking traditional NSAIDs for at least two months will die from G.I.-related complications. A conservative estimate: 16,500 NSAID-related deaths occur every year in the United States, approximately equivalent to the number of deaths from AIDS.

The holy grail of anti-inflammatories would be a COX inhibitor without this side effect. This became a real possibility in 1990, when COX was shown to exist as two chemically distinct enzymes COX-1 and COX-2. COX-1 protects the G.I. tract, while COX-2 is responsible for the inflammatory response. The obvious answer to the G.I. complications: develop a drug that inhibits COX-2 but not COX-1.

Give Merck credit. It developed Vioxx, a drug with the same degree of anti-inflammatory and anti-pain response as NSAIDs, but with a significant reduction in G.I. complaints and complications.

But medicine rarely comes in such neat categories. As far back as 1984, Garret FitzGerald and his colleagues at the University of Pennsylvania, writing in the New England Journal of Medicine, showed that the COX enzyme might prevent arterial blood clot formation. FitzGerald suggested that this side effect might mean little in healthy persons but could be dangerous to patients with severe atherosclerosis. Which sounds reasonable a high level of an anti-clotting enzyme wouldn't be necessary in normal vessels, but would be necessary in damaged vessels in which clot formation was more likely.

In 1997, with Vioxx still in clinical trials, FitzGerald himself consulted with Merck. According to Merck's position statement, recently filed in a U.S. District Court in Louisiana, in response to a class-action lawsuit, FitzGerald warned the company that COX-2 had a possible anti-clotting benefit. He expressed concern that suppression of this mechanism by a "coxib" drug such as Vioxx might increase the risk of blocked arteries.

Merck responded to FitzGerald's research by re-analyzing all of its Vioxx clinical data, and included FitzGerald's potentially worrisome lab data in its FDA application. (This data was published in 1999 in the Journal of Pharmacology and Experimental Therapeutics.) Merck also declared that it had adopted the standard procedure for "facilitating rigorous scientific analysis, on an ongoing basis, of all competing hypotheses about potential CV risks or benefits from Vioxx."

Was this a sufficient evaluation of a potentially serious side effect of Vioxx? Or should more have been done? Given that it is standard practice to assess all serious potential risks of new drugs, FitzGerald's concern should have been directly addressed.

But rather than design a study focused on the C.V. risks of Vioxx, Merck created the VIGOR (Vioxx Gastrointestinal Outcomes Research) study in 2000. It compared the incidence of G.I. complications of Vioxx to naproxen, another conventional NSAID, whose most popular brand is Aleve. The goal was to prove that Vioxx was an equally effective but safer drug than an over-the-counter NSAID. Unfortunately, the study, published in the New England Journal of Medicine, revealed a twofold increase in C.V. risk for patients who took Vioxx. Of course, Merck acted surprised. What Merck didn't tell us is that it had stripped the deck of patients at high risk for heart disease.

In the VIGOR study, 80 percent of patients were women with an average age of 58, with Merck being well aware that women, on average, develop C.V. disease 10 years later than men. Only 4 percent of the total subjects had a prior history of C.V. disease and were felt to be at high risk for further C.V. events. It was no surprise, then, that 38 percent of the heart attacks in the group of patients who took Vioxx came from this small 4 percent subgroup.

Ironically, it was Merck's failure to eliminate these few high-risk patients that allowed the C.V. effects of Vioxx to be detected. According to a review of coxibs in the New England Journal of Medicine, published in 2001, if these few high-risk patients had been excluded from the VIGOR study, the difference between Vioxx and naproxen would not have been significant. Therefore Vioxx may have never been taken off the market.

But there's more.

Anyone who's gambled in a casino knows that the key to winning is to get lucky initially and quit before the odds catch up with you. Get in and get out before the odds get a chance to declare themselves.

To understand the risks involved with a coxib, it is necessary to conceptualize risk as a function of time. The risk of electrocution is immediate. You don't grab a hot wire and get electrocuted next year. It's now or never. Similarly, a fatal allergic reaction to a penicillin injection happens within minutes, not in six months. In assessing risk factors with a predictable time of occurrence, it is easy to determine the study period. But other risks can take years or decades to manifest themselves.

It took many years to recognize the detrimental effects of hormone replacement therapy, or the time lag between sun exposure and the subsequent development of a malignant melanoma. Such correlations require following large groups of patients for extended periods of time. A major source of our understanding of cholesterol levels and the development of C.V. disease came from large-population longitudinal studies such as the Framingham Heart Study, which began in 1948 and is still ongoing.

It is self-evident that risk factors can be present for many years before becoming clinically observable. Although elevated levels of cholesterol increase the risk of a heart attack, the rate of heart attacks in teenagers with high cholesterol is far less than that of middle-aged adults with similar cholesterol levels. The cholesterol effect is cumulative; atherosclerosis takes time to become manifest.

If we wanted to minimize or negate the apparent effect of cholesterol on heart disease, we would study the youngest patients we could, and for the shortest period of time. If we ran a nine-month study to compare the incidence of heart attacks in a group of 10-year-olds with high cholesterol vs. normal controls, it is highly unlikely that we would see a difference.

The Framingham study has been ongoing for more than 50 years. Merck's VIGOR study followed its patients for an average of nine months. Even this short period revealed a very disturbing trend.

During the first six weeks of the study, there was no significant difference between the two drugs. As the follow-up period continued, the patients taking naproxen clearly were having fewer heart attacks than those taking Vioxx. But between months 8 and 11, the naproxen rate was relatively constant, while the Vioxx rate appeared to be accelerating. It was at this critical point that Merck concluded its trial.

When asked why it concluded its VIGOR study at this key juncture, a Merck spokesperson replied with a terse e-mail: "VIGOR was an endpoint-driven study and it ended when it was designed to end."

Merck repeatedly contended that it was actively investigating possible reasons for the adverse findings in the short VIGOR study. One of them was that the difference between Vioxx and naproxen could be best explained as a cardio-protective benefit of naproxen as opposed to an untoward side effect of Vioxx. Most researchers disagree. To date, no large-scale study has demonstrated more than a possibly small protective effect of naproxen, and certainly not of the magnitude that would explain the VIGOR difference. In fact, a recent study of naproxen and prevention of Alzheimer's disease was halted because of an apparent increase in C.V. events.

Listen to Peter S. Kim, president of Merck Research Laboratories, explain why Vioxx had a higher C.V. complication rate than naproxen. "Because the VIGOR study compared two drugs Vioxx and naproxen and did not contain a placebo arm, it was not possible to conclude, based on this study alone, whether naproxen was having a beneficial CV effect or whether Vioxx was having a detrimental CV effect."

When I asked Merck why it didn't include a placebo group in the study, which would have underscored the C.V. effects of Vioxx, it referred me again to its court statement: "For ethical reasons, Merck could not conduct a placebo-controlled study in a population that required pain medicine (because patients in the placebo arm would receive no pain relief)."

Yet placebo control studies are commonly used to study anti-pain medications. Indeed, many peer-reviewed osteoarthritis and rheumatoid arthritis studies of NSAIDs and coxibs, including Vioxx, have included a placebo group for comparison. (Unfortunately, these studies were of too short a duration 6-12 weeks to assess any long-term C.V. effect. Merck, nevertheless, cites the data to show no evidence of C.V. effect of Vioxx.)

In an August 2001 article in the Journal of the American Medical Association, Drs. Mukherjee, Topol and Nissen from the Cleveland Clinic compared rates of heart attacks in trials performed with selective COX-2 inhibitors, including Vioxx, to heart attack rates compiled from a large number of studies on aspirin for heart disease prevention. Their review included 48,000 patients; the Merck VIGOR trial had 8,000.

The authors concluded: "The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors." Even more compelling, they stated: "We believe that it is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents. Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular morbidity."

Merck did make a motion in that direction. According to an article in the New York Times earlier this year, the company planned to initiate a major C.V. risk study called VALOR in 2002. But just days before company researchers were to submit the study's protocol to the FDA, the project was abruptly halted. Merck did not explain why. It issued a general statement, saying that as it was designing the study, "we continued to ask ourselves and our consultants whether this was the right way to definitely answer" the question of whether Vioxx posed C.V. risks. "We ultimately decided not to conduct that particular study."

In 2002, with Vioxx selling extremely well, Merck was no doubt convinced that the odds of keeping the painkiller on the market remained in its favor. After all, when the VIGOR study revealed that patients who took Vioxx showed a twofold increase in heart attacks, Merck must have figured that it could face potential lawsuits. Just as all Big Pharma companies do, Merck must have calculated that profits from sales would outweigh losses from lawsuits.

In fact, as a study in the Archives of Internal Medicine would later show, Merck, through heavy promotion, sought to create as wide a market as possible for Vioxx. (The study revealed that 73 percent of people who took Vioxx did not need a coxib, that a standard NSAID like aspirin would have been sufficient.) Apparently, selling Vioxx as a niche drug for people who really did suffer G.I. problems from NSAIDs, and who were at low risk for heart disease, did not meet Merck's profit-and-loss forecast.

Merck initiated several more studies of Vioxx, all primarily intended to uncover further potential markets for the drug. In each case, it avoided delving specifically into possible C.V. complications. Most notable was the APPROVe study, which looked toward the prevention of colon polyps, as well as other studies for possible treatments for colorectal and prostate cancer.

In September 2004, when the APPROVe trial revealed the same twofold increase in C.V. complications as the VIGOR study, Merck recalled Vioxx. Even then, Dr. Alise Reicin, vice president of clinical research at Merck, reiterated that this was a puzzling finding. She said that Merck has so far been unable to identify a mechanism behind the increased risk. The fact is that Merck avoided initiating studies to find one.

To further distance Merck from any responsibility for those who had recently begun taking Vioxx, Kim added, "While the cause of these results is uncertain at this time, they suggest an increased risk of confirmed CV events beginning after 18 months of continuous therapy."

No, the risk didn't begin after 18 months. This would be analogous to saying that daily sunbathing for 18 months poses no risk for melanoma if no melanomas are detected during that time, and that the risk doesn't begin until the melanomas are first discovered. The risk is present from the beginning but only evident at 18 months.

Finally, Merck is asking us to believe that it didn't suspect from the outset that Vioxx might increase the risk of heart attacks and strokes. It's telling us that its studies were adequately designed to detect both the incidence and possible underlying mechanisms of cardiovascular risks. It wants us to accept that a nine-month study, abruptly concluded, was insufficient evidence for the withdrawal of Vioxx because it was reasonable to presume that naproxen had a cardio-protective effect.

For me, the sad but inescapable conclusion is that Merck made an informed decision to avoid knowing the full extent of Vioxx's potential risks for heart attacks and strokes.

And the FDA was either extraordinarily lax or frankly complicit. In April 2002, the federal agency did state that Merck must affix a new label to Vioxx, advising doctors to use caution when prescribing it to patients with heart disease. But it didn't rule that the drug be withdrawn from the shelves.

Based upon their review of available data about Vioxx, a team of medical scientists from the University of Berne, Switzerland, published this summary in a December 2004 issue of Lancet: "Our findings indicate that Vioxx should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarize the accumulating evidence need to be clarified."

This situation is not likely to change. On at least three occasions, Congress has voted to approve partial FDA funding by pharmaceutical companies. Beginning in 1992 with the passage of PDUFA the Prescription Drug User Fee Act pharmaceutical companies have been paying up to $500,000 for each new drug application. Currently, greater than 50 percent of drug reviewers at the FDA are funded by the pharmaceutical industry.

According to the Center for Science in the Public Interest, 10 of the 32 FDA advisory board members who, in 2005, recommended the continued sale of coxibs, had previously consulted for Merck, Pfizer or Novartis. (Pfizer and Novartis have not withdrawn their coxibs, Celebrex and Prexige, respectively, from the market.) To be fair, this isn't entirely damning, as many top researchers have ties with pharmaceutical companies yet maintain unbiased positions. Dr. FitzGerald, one of Merck's harshest critics, has received research funding from Merck.

When Merck withdrew Vioxx, the FDA responded: "The risk that an individual patient taking Vioxx will suffer a heart attack or stroke related to the drug is very small." This is both true and profoundly misleading.

A truly independent agency for the evaluation of new drugs is essential. But the unfortunate truth for the foreseeable future is that we are dependent upon the pharmaceutical industry and its hired security guards the FDA to police itself.

We are not helpless. We do have one ace in the hole the simplest and most difficult of questions. Do I need this medication? Or, as Ray would say, is this the only game in town and do I need to play?

If you have rheumatoid arthritis and can barely dress and feed yourself, a doubled chance of a heart attack on Vioxx might be an acceptable trade-off for increased mobility. A disabling stroke, no matter how unlikely, doesn't seem like a reasonable risk for a twinge of tennis elbow.

The decision to take any medication is highly personal, a reflection of everything from genetic predispositions to cultural values to the loftiest of metaphysics. It cannot depend exclusively upon statistics. An honest and thorough medical system can provide the information, but the old saw, know thyself, is essential to such choices.

So is know thy playing partner.

And the key to making the right personal decision is that we need transparency of data. We need to get our hands on the deck and look for ourselves. There are plenty of smart and independent folks who could sift through the information and give us an informed opinion. We must demand that study data be made publicly available to those without a vested interest.

The best place to start is with your own family doctor. If you and your physician had adopted Ray's approach to medication, you would have known in August 2001 that leading cardiologists such as Dr. Topol had major concerns about possible Vioxx C.V. effects. And you would have carefully discussed the labeling change ordered by the FDA in 2002. Unless you are an Internet health letter, medical journal junkie, only your doctor would have received this news in a timely fashion.

However, the problem of post-approval drug side effects will not go away. After 30 years on the market, it is still unclear as to the C.V. effects of the allegedly "safe" NSAIDs such as Aleve. We have to anticipate the unknown, accept certain knowledge limitations, and trust someone to be our advocate in an ever more confusing medical landscape. And we need to balance a well-deserved skepticism with an equal appreciation of what modern medicine has accomplished.

In the big picture, Merck has had an outstanding reputation. It offers a variety of formidable drugs that both improve and save lives. As a niche drug, prescribed to those unresponsive to the older NSAIDs, or to those with unacceptable G.I. complaints or at high risk for ulcers or bleeding, Vioxx would have been a good alternative. If the properly designed studies had been carried out, and we had been given full and prompt access to the data, we could have made our own smart choices. It's a tragedy that Vioxx led to fatal heart attacks and strokes. And it's a sad irony that those who were clearly benefiting from the drug no longer find it available to them.

Warnings On Popular Pain Killers

Wed, 23 Mar 2005 00:00:00 -0800

The American Heart Association is weighing in on the controversy surrounding the link between pain killers and heart problems, offering its own recommendations for patients taking prescription medications like Celebrex and Bextra.

Their recommendation is to use the drug with the fewest known risks, The Early Show medical correspondent Dr. Emily Senay explains. That's very important and that may vary from patient to patient. So you need to think very carefully about your individual patient and what their risk factors are. Then physicians should limit the usage.

The concern is that patients are overdoing it with pain medication. Most of these recent studies linking cardiovascular disease to pain killers have studied usage over a long period of time. And the findings indicate that the risk of suffering heart problems increases with the length of the usage. So you can keep the chances of experiencing cardiovascular problems by limiting your exposure and taking a low dosage.

While studying the possibility that Celebrex and Bextra might be beneficial in cancer prevention, researchers saw an increased risk for heart problems. Two different studies one from Brigham and Women's Hospital and Harvard Medical School and another from the Texas Heart Institute found patients who took these drugs had an increased chance of suffering a heart attack or other cardiovascular problem.

And back in February, an advisory panel for the Food and Drug Administration ruled that the painkillers are believed to pose an increased risk for heart problems. But they claim that the benefits outweigh the dangers and therefore the drugs should stay on the market. A third drug, Vioxx, was taken off the market voluntarily by its manufacturer in September of 2004.

The American Heart Association is not saying to avoid these medications at all costs, but they do recommend searching for a safer alternative before relying on Celebrex or Bextra for pain relief.

The first choice should be to try an over-the-counter pain reliever such as aspirin, acetaminophen, or ibuprofen. They are proven to be safe and effective for pain relief. But again, you need to ask you doctor about which ones are right for you.

Every drug has side effects, and you need to pay attention to the directions and take the doses recommended by the manufacturer. Remember, aspirin is widely recognized for its protective benefits when it comes to heart disease. That's becase of its blood-thinning qualities that help prevent the clogging of arteries. Low doses of aspirin already are widely prescribed to prevent heart attack or stroke in people who already have cardiovascular problems.

The American Heart Association says physicians really need to keep in mind the risk factors associated with Celebrex and Bextra. In addition to the patient, doctors should also be looking for safer alternatives and should weigh the benefits and risks before prescribing Celebrex or Bextra.

Caution Urged On Alternative Painkillers

Tue, 08 Mar 2005 00:00:00 -0800

As patients have turned to other painkillers to avoid the cardiovascular risks associated with Vioxx, Bextra and Celebrex, scientists are casting suspicion on several of the substitutes, especially Mobic.

Prescriptions for Mobic have tripled since September, when the maker of Vioxx voluntarily withdrew the COX-2-inhibiting painkiller because of findings of heart problems. Immediately, the maker of Mobic began courting former Vioxx users, through ads and company representatives' visits to doctors.

The marketing push paid off, making Mobic the fastest growing prescription drug for arthritis. Its share of new prescriptions soared from 5 percent to 19 percent, as of last month.

Weighing benefits, risks

But is Mobic safer than Vioxx, Bextra or Celebrex, which are all COX-2 inhibitors? Some researchers and doctors have expressed doubts. They say Mobic (meloxicam) and several other painkillers may actually work in similar ways and pose similar risks.

"I think they need to be looked at more closely," says University of Texas Southwestern gastroenterologist Byron Cryer, an expert on painkiller risks. "These drugs are getting a get-out-of-jail-free card."

Last month, a Food and Drug Administration advisory panel decided Vioxx, Bextra and Celebrex have significant cardiovascular risks, recommending the agency limit their use, but not recommending removal from the market. FDA action is expected within weeks. Agency officials say that as part of a review of all non-steroidal anti-inflammatories (NSAIDS), they are examining Mobic and similar drugs.

Researchers and public health advocates generally mention five drugs as potentially in the COX-2 inhibitor class: Mobic, diclofenac, etodolac, nabumetone and nimesulide.

Elsewhere, officials have gone further. Australia's drug regulatory agency, the Therapeutic Goods Administration, has placed Mobic in the COX-2 family.

"Meloxicam should not be prescribed for patients with increased risks of cardiovascular events such as heart attacks, and treatment should be limited to the shortest time needed," said University of Sydney Professor Dr. Martin Tattersall.

Vioxx, Bextra and Celebrex are classified as COX-2 inhibitors because they block the cyclooxygenase-2 enzyme. (All anti-inflammatory drugs block this substance, but the so-called COX-2 inhibitors do so more selectively.) When the COX-2 inhibitors first appeared in the late 1990s, pharmaceutical companies aggressively marketed them, emphasizing that the medicines seemed to have fewer gastro-intestinal side effects than older painkillers. The new products became top sellers.

New drugs are COX-2 blockers

Last fall, however, being a COX-2 inhibitor became a liability. Several studies found that the drugs raised the risk of heart attack and stroke. It turns out that the COX-2 enzyme has a dual role: It triggers pain and inflammation, but it also seems to protect the heart, perhaps by keeping blood thin or lowering blood pressure. So blocking it can decrease pain, though perhaps with a price.

Vioxx, Bextra and Celebrex aren't the only drugs that selectively inhibit the COX-2 enzyme. Researchers say that Mobic and some other painkillers, such as diclofenac, are also strong COX-2 blockers, even though they haven't been marketed as such.

Referring to Mobic and diclofenac, University of Pennsylvania pharmacologist Garrett FitzGerald said they would likely turn out to be "Celebrex in sheep's clothing." FitzGerald, also a cardiologist, is an expert on COX-2 inhibitors and heart disease.

The drugs' makers say their products are safe. "We are confident in Mobic. We have observed no trends that indicate an increased risk," said John Yonsky, a spokesman for Boehringer Ingelheim Pharmaceuticals, the German company that makes the drug and, along with Abbott, markets it in the United States.

Wyeth Pharmaceuticals spokesman Lowell Weiner defended etodolac, which is sold by the company under the name Lodine.

"Lodine is a non-steroidal anti-inflammatory drug. It is not a COX-2 inhibitor," he said. "Wyeth stands by the safety of Lodine." Most of the attention has so far focused on Mobic and diclofenac, which is sold as Voltaren. At the FDA's COX-2 hearing, FDA safety officer Dr. David Graham singled out Mobic.

Mobic as risky as Vioxx?

In a study that has yet to be published, he and a collaborator examined heart attack risks among 650,000 Californians taking pain relievers. They found that Mobic appeared to be as risky as Vioxx, which is generally seen as the COX-2 inhibitor that is the most dangerous to the heart.

Graham emphasizes that one study is not enough to prove that a drug is dangerous, yet says the results should encourage cautious use and more research: "If you've got lots of people using it, you want to find out if it's safe."

Watchdog Pulls Pain Killer

Tue, 08 Mar 2005 00:00:00 -0800

Health Canada yesterday joined U.S. and European regulators and ordered Pfizer to pull the drug Bextra off the market until concerns about its safety profile can be answered.

The move follows a public advisory last December indicating serious, potentially life-threatening skin reactions had been reported in patients taking Bextra.

In a conference call yesterday, a Health Canada official said the agency has found seven to nine cases of severe skin reactions associated with Bextra since 2002. None were fatal.

Regardless, anyone taking Bextra was encouraged to contact their doctor to discuss alternatives. The federal regulator also recommended new restrictions for Pfizer's Celebrex, warning of possible increased cardiovascular risks.

"We disagree with their position but we're complying with their request," said Pfizer's Michael Amos, adding the company hopes to persuading Health Canada to allow Bextra back on the market.

ANTI-INFLAMMATORY DRUGS

Introduced in Canada in 2002, Bextra is a member of the class of anti-inflammatory drugs known as COX-2 inhibitors, as is Celebrex. Bextra is used to treat arthritis and menstrual cramping.

When first approved in Canada in 1999, COX-2 inhibitor drugs were touted as "super aspirins" because they could relieve pain and inflammation like aspirin and other traditional (non-selective) NSAIDS, without causing stomach problems.

Since last September, however, the drugs have been embroiled in controversy. It began when Vioxx was pulled from the market by its maker after studies linked it to increased risk of heart attack and stroke. That's when Health Canada's scientific review began.

Since then, studies have suggested the risk is a class effect, meaning all the drugs in the class increase risk of cardiovascular events but, it is thought, to differing degrees.

Only one of the drugs, Celebrex, remains on the market in Canada.

At the Ottawa Hospital, however, Dr. Doug Smith, head of rheumatology and the Arthritis Centre, says although he's pleased that the drugs are under scrutiny, he feels regulators are being particularly cautious after Vioxx.

"There are certain populations of patients who have benefited tremendously from this class of drugs. (But) with any drugs there are risks and benefits and you always have to weigh those," Smith said.

RECENT DRUG WARNINGS

Dec. 17, 2004: Health Canada warns patients using Celebrex of increased cardiovascular risks when the drug is taken at daily doses of 400 mg and 800 mg.

Dec. 22, 2004: Health Canada releases another warning about selective COX-2 inhibitor NSAIDs. The agency states that evidence indicates that the use of them, in certain individuals, is associated with an increased risk of heart attack or stroke when compared to a placebo.

February 2005: FDA panel concludes Celebrex, Bextra and Vioxx all pose a risk to the heart, but should be available to consumers.

April 7, 2005: FDA and Health Canada ask Pfizer to withdraw Bextra from the market.

FDA Seeks Drug-Warning-Label Authority

Tue, 01 Mar 2005 00:00:00 -0800

The Food and Drug Administration asked Congress on Tuesday for authority to dictate label changes for drugs to end the type of haggling with pharmaceutical companies that delayed warnings to Vioxx users about potential heart problems.

Sandra L. Kweder, FDA's deputy director for new drugs, told the Senate Committee on Health, Education, Labor and Pensions that the ability to require changes in labels "would be helpful."

After the dangerous side effects of Vioxx were known, negotiations between the FDA and its manufacturer, Merck & Co., over what a warning should say, delayed getting the information out.

"The lapse from my perspective was the delay that it took to get that information into the labeling," Kweder told the panel. "We had to negotiate with the company how the specific language should be worded."

The authority to dictate the labeling language would have helped, she said, but so would the Bush administration's newly announced policy to publicize warnings before such sticking points are worked out.

Merck pulled Vioxx from the market Sept. 30 after heart problems were reported in some users. Similar questions were later raised about other so-called Cox-2 inhibitors Bextra and Celebrex prompting the FDA to have an advisory panel to look into the matter.

The advisory panel on Feb. 18 decided that the arthritis drugs' benefits outweighed its risks of heart problems and strokes but suggested the products carry strong warnings.

On Monday, Massachusetts-based Mogen Idec Inc. and Elan Corp. announced they were pulling a drug to treat multiple sclerosis after it triggered a serious disease in two patients killing one of them when taken with other drugs.

Congress is considering legislation to tighten rules on how the government keeps track of the safety of drugs after the FDA approves them.

The Bush administration announced last month it will set up an independent Drug Safety Oversight Board to monitor FDA-approved medicines once they're on the market and update physicians and patients with emerging information on risks and benefits.

Was Painkiller Panel Stacked?

Fri, 25 Feb 2005 00:00:00 -0800

Almost a third of the members of a government panel that voted last week to let the pain pills Celebrex, Bextra and Vioxx stay on the market recently consulted for the makers of the drugs, The New York Times reports.

According to the report, disclosures in medical journals and other public records show that ten of the 32 panel members have done some work for Merck, the maker of Vioxx; Pfizer, the maker of Celebrex and Bextra; or Novartis, which is applying to sell Prexige, a similar type of medication.

Without the votes of those 10 members, the committee would have voted 12 to 8 that Bextra should be withdrawn and 14 to 8 that Vioxx should not return to the market. The 10 advisers with company ties voted 9 to 1 to keep Bextra on the market and 9 to 1 for Vioxx's return.

The Food and Drug Administration advisory panel said last Friday that all three scrutinized Cox-2 drugs pose cardiovascular risks, but still voted to keep them on the market.

The decisions surprised many analysts, CBS News Medical Correspondent Elizabeth Kaledin reports.

The one thing panel members almost unanimously agreed on is that the drugs must be used under the strictest warnings and tightest supervision, pushing for black box warning labels that let the people know that these drugs can help but can't be taken lightly, Kaledin reported.

The vote for Bextra was 17-13 with two abstaining. While the Vioxx decision was the closest, 17-15, Celebrex passed the panel's approval easily, 31-1.

The FDA panel's actions came during a three-day meeting to discuss the safety of pain relievers. Analysts had anticipated that studies linking Celebrex to greater risk of heart attack and stroke might lead the panel to recommend a so-called black box warning, the highest level of warning at the FDA, for the Pfizer drug. Since Celebrex sales have already fallen dramatically since the risk emerged, analyst don't believe the warning will have a big effect on its revenue.

Bextra already has a black box warning.

Vioxx, Celebrex and Bextra are Cox-2 inhibitors, a category of painkiller medication. When Merck voluntarily recalled Vioxx in September 2004, it was the only one in the group that showed cardiovascular risks. Since then, several studies have linked Celebrex and Bextra to the same risks.

Cox-2 inhibitors were developed to be gentler on the stomach than older pain relievers, though only Vioxx received FDA permission to include that claim on its label. That benefit is one reason doctors still like the drug.

The panel's recommendation came despite some strong words against Cox-2 inhibitors, and Vioxx in particular, from prominent critics. FDA whistleblower Dr. David Graham said: "there doesn't appear to be a need for Cox-2" inhibitors.

Graham authored a study published in Lancet, which said Vioxx caused an estimated 88,000 to 140,000 excess cases of serious heart disease in the U.S. while it was on the market.

Meanwhile, meeting chairman Alistair J. J. Wood of Vanderbilt University Medical School said, "The data are very compelling, Vioxx is substantially worse than the others."

According to the Times report, before the panel meetings an F.D.A. secretary read a statement absolving members of conflicts of interest because the agenda involved "issues of broad applicability and there are no products being approved."

Last year, Celebrex sales leapt 75 percent to $3.3 billion. In December, during the week when word of its cardiovascular risk became public, Celebrex claimed 44 percent of prescription pain killer sales in the retail market with revenues of $44 million. By the week ended Feb. 11, Celebrex's share fell to 23 percent with sales of $24 million, according to Verispan, which tracks prescription drug information.

Health Canada Too Slow On Drug Safety: Experts

Wed, 23 Feb 2005 00:00:00 -0800

Researchers who submitted a plan to Health Canada last year to improve drug-safety monitoring complain that the federal department has been too slow to act on it.

Over the past year, as concerns grew around the heart risks of popular cox-2 painkillers, including Vioxx, Health Canada was processing a proposal from university researchers to cull information about drug safety and drug use from the health-care system's databases.

FDA whistle-blower scientist David Graham used similar information from a health management group to reach the conclusion last summer that Vioxx could have caused more than 80,000 heart attacks in the United States.

Toronto researchers also used database information in 2003 and found that Ontario seniors who took Vioxx faced an 80-per-cent increased risk of being hospitalized for heart failure.

The databases contain information doctors and hospitals submit for reimbursement to provincial governments about their patients and the treatments they receive.

Analyzing the information allows researchers to make connections between drugs and potential side effects.

Health Canada officials were receptive to the plan at meetings that began last winter, but "long pauses" followed with department staff not returning e-mails or phone calls on the issue.

"It was just silence," said Muhammad Mamdani, a senior scientist at the Institute for Clinical Evaluative Sciences in Toronto. "There was an incredible amount of frustration from academics [involved in the plan] about how quickly they weren't moving."

Only in the wake of the public controversy that has erupted over Vioxx, which Merck & Co. stopped selling last fall after finding it doubled the risk of heart attack and stroke, has Health Canada renewed correspondence on the safety plan, said Dr. Mamdani, citing an e-mail that department officials sent Jan. 31.

"Had the cox-2 drug controversy not happened, it's my opinion that Health Canada might still not be moving quickly," he said.

But Health Canada spokeswoman Jirina Vlk defended the department, saying officials have been in communication with the researchers and, "the idea of a network is very much alive."

She said Health Canada officials are to meet provincial drug-plan managers next week and academic experts on drug safety in the spring.

"The [Health] Minister and the department take the issue of drug safety very seriously," she said, adding that the network could complement other reforms under consideration.

Health Minister Ujjal Dosanjh said last fall, for example, that he may make it mandatory for doctors to report adverse drug reactions. Physicians now report such information on a voluntary basis.

John Hoey of the Canadian Medical Association said the current system tends only to turn up the very unusual, or rare and unexpected adverse reactions.

"How do you connect the dots [to a drug] if someone is 65 or over, and maybe at risk of a heart attack anyway?" Dr. Hoey asked, in reference to the difficulty of spotting the heart-risk link that cox-2 drugs carried.

Geoffrey Anderson, a University of Toronto professor in the faculty of medicine, and one of the lead architects of the national drug monitoring proposal sent to Health Canada, said data base information could allow researchers to recognize trends in adverse events and conduct studies about the way a drug is used and what happens to patients who use it.

He noted that the plan, estimated to cost $2-million a year, with researchers' salaries covered by their institutions, is not an expensive one.

Dr. Anderson said he is aware that Health Canada officials are gathering input from provincial officials, and called such consultation "laudable." But, he said, "safety is clearly a federal mandate."

"They are doing something, but they could do more and they could do it faster," he said. "It's particularly frustrating if you are an academic and you want to do [work] that really affects policy and the safety of Canadians."

He noted, for example, that after Health Canada released a public advisory on Jan. 21 about cardiovascular risks linked to the dementia drug Reminyl, researchers called the department offering to study databases for information on adverse events.

"There really hasn't been much of a response. We weren't asking them for money, we were just asking to be partners in this," Dr. Anderson said. "It shouldn't be like us phoning them up and asking them if we can help them. There should be a linking between the academics who do this work and the people who have to make the decisions to protect the Canadian public."

Regulators have been harshly criticized for failing to act sooner on safety concerns surrounding cox-2 drugs and doctors are now considering various ways to boost drug-safety monitoring.

Claire Bombardier, director of rheumatology at the University of Toronto and a key consultant to Merck on the Vioxx file, said in a recent interview with The Globe and Mail that Health Canada should perhaps grant only conditional approval to new drugs. The condition, she said, would be based on large, long-term patient studies demonstrating the medication is relatively safe.

But Dr. Mamdani cautioned that any postmarket studies of a medication should be carried out by an independent body: "Health Canada just doesn't have the people to keep track of what information they would need and they are not organized to do that."

Celebrex Heart Attack Lawyer Stroke Lawsuit Attorney

Wed, 23 Feb 2005 00:00:00 -0800

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Celebrex (Generic: Celecoxib) is a COX-2 inhibitor, a class of drugs linked to an increased risk of blood clots, heart attacks and strokes. Celebrex is the only COX-2 inhibitor still on the market in the United States. Celebrex and the recently withdrawn Bextra are both marketed by the Pharmacia Corporation and Pfizer Inc. in the United States. Celebrex and the other COX-2 inhibitors are prescribed for the treatment of osteoarthritis, adult rheumatoid arthritis, and the pain associated with menstrual cramping.

In February 2005, the FDA asked advisory committees to examine the COX-2 inhibitors and to determine whether they offer enough benefits to stay on the market, whether they need stronger warnings, and what further research on the drugs is needed. The advisers met from February 16, 2005 through February 18, 2005. Studies "strongly suggest" the entire class of drugs called COX-2 inhibitors elevates the chances of cardiovascular problems, Dr. Ned Braunstein, senior director of Merck Research Laboratories told the panel of FDA advisers.The hearings concluded and both Celebrex and Bextra were allowed to stay on the market. However, on April 7 the FDA asked Pfizer to withdraw Bextra from the market, citing reports of cardiovascular events and allergic skin reactions. When Pfizer agreed to suspend sales of Bextra, Celebrex became the last COX-2 inhibitor to remain on the market.

A study from the Cleveland Clinic appeared in the Journal of the American Medical Association and was based on an analysis of previous clinical trials. In a study of more than 8,000 patients that compared the COX-2 inhibitor rofecoxib (Vioxx) with the traditional NSAID naproxen, the risk of cardiovascular problems, including heart attack, chest pain related to heart disease, stroke, sudden death and blood clots, was more than two times higher in the rofecoxib group than in the naproxen group. Merck voluntarily withdrew Vioxx in September 2004 after a study found that the drug doubled the risk of heart attack and stroke in patients who took it for at least 18 months. Following the Vioxx recall, questions arose about Celebrex, Bextra, and non-prescription pain relievers such as Naproxen (Aleve).

Dr. Garret Fitzgerald, a top scientist and COX-2 researcher at the University of Pennsylvania, told the US regulatory panel that all pain drugs in the class known as COX-2 inhibitors increase the risk of heart attacks and strokes. Dr. Fitzgerald has said that the body reacts in the same way to drugs including Merck's Vioxx and Pfizer's Celebrex and Bextra. Dr. Fitzgerald said the drugs create an imbalance in the body's cardiovascular system that leads to an increased risk of heart attacks and strokes.

The annual rates of heart attack in both the Celebrex (celecoxib) and Vioxx (rofecoxib) studies were increased compared to a review of studies containing a total of more than 48,000 patients. In those studies, 0.52% of patients taking an inactive placebo pill had a heart attack each year. The annual rate of heart attack was 0.74% for patients taking rofecoxib and 0.80% for those taking celecoxib.

On March 1, 2006, a group of researchers in New Zealand said that a reanalysis of older studies conducted on Pfizer's pain reliever Celebrex show the drug can raise the risk of suffering a heart attack. Researchers from New Zealand's Medical Research Institute in Wellington said that the analysis, which used data from past Celebrex clinical trials, showed the drug could nearly double the risk of heart attack in patients, according to local reports.

The analysis utilized data from six studies on Celebrex involving 12,780 users. The results were published in the Journal of the Royal Society of Medicine.

Pfizer has said it expects 2006 sales of Celebrex to be in excess of $2 billion.

If you or a loved one took Celebrex and suffered side effects, please fill out the form at the right for a free case evaluation by a qualified drug side effects attorney.