The Bitter Pill

The Official Blog of UNITE – uniteforlife.org

Zyprexa Judge Sends Invite to NY Times Reporter

Evelyn Pringle February 1, 2007

The judge in the Zypexa secret document case has sent a New York Times reporter an invitation to attend a hearing in the on-going Eli Lilly fiasco in the US District Court for the Eastern District of New York.

“This invitation,” Judge Jack Weinstein wrote, “is intended to permit Alex Berenson to confront testimony received at a hearing in this court on January 16-17 implicating him in a conspiracy to obtain and publish confidential documents sealed by this court.”

According to Lilly, it took no part in extending this invitation. However, since when does a judge send out invitations, unsolicited by either side in litigation, to witnesses or by the sounds of it a potential defendants?

Mr Berenson most likely earned the invite in December 2006, when he published several articles exposing the fact that for a decade, Eli Lilly had failed to warn consumers, members of the medical profession, and the FDA, about risks of severe weight gain, blood sugar problems, and diabetes associated with Zyprexa.

Mr Berenson also reported that Lilly had illegally promoted Zyprexa for off-label uses not approved by the FDA, quoting Lilly’s own internal documents as his source.

For years, Lilly has been allowed to keep this information hidden, while settling thousands of cases out of court, by falsely claiming that the millions of documents produced during litigation contained trade secrets and getting judges to seal them all with protective orders.

In what can only be considered a heroic act, an expert witness in the Zyprexa litigation, Dr David Egilman, apparently helped facilitate the outing of some of the secret documents when he provided them to attorney, Jim Gottstein, who then provided them to Mr Berenson at the New York Times.

Being Mr Egilman is doctor, when it became obvious that Lilly was going to continue to keep this information secret, after settling out of court with the second round of Zyprexa victims, it can easily be understood why he would believe certain documents had to be made public.

Doctors take an oath to do no harm. Allowing Lilly do go on marketing Zyprexa off-label for every ailment known to mankind without fully warning the public about the serious health risks associated with the drug would have resulted in many more injuries and deaths without a doubt.

A sincere desire by a doctor and an attorney to find a way to warn the public about a dangerous drug does not constitute a conspiracy by any stretch of the imagination.

The only evil conspiracy here involves Lilly’s off-label marketing of Zyprexa to the extent that it took a drug approved for the extremely limited indications of treating adults with schizophrenia or manic depression and turned it into its number one selling product.

In regard to the out-of-court settlements, which to date have cost Lilly about $1.2 billion, Lilly’s chief executive, Sidney Laurel, said in a January 4, 2007 press release: “While we remain confident that these claims are without merit, we took this difficult step because we believe it is in the best interest of the company, the patients who depend on this medication, and their physicians.”

“We wanted to reduce significant uncertainties involved in litigating such complex cases,” he stated.

Lilly’s press release expressed no remorse, only more denial, even when the secret documents quoted in the media at that time substantiated every allegation made by the plaintiffs in the cases that were settled out of court.

In the first two rounds of litigation combined, the company has reportedly settled with about 26,500 plaintiffs, but round three is coming up. According to Lilly‘s SEC filings, approximately 1,200 more claims have been identified that are not included in the settlements.

In a January 15, 2007, legal filing, Lilly attorneys claim the Zyprexa documents are not widely disseminated in stating: “Despite a concerted effort by a small group of individuals to take advantage of Dr. Egilman’s and Mr. Gottstein’s violation of CMO-3, and to violate the Temporary Mandatory Injunctions, this effort fell flat.”

Wrong. Any reporter who wants the documents can get them off the internet within a hour max. Furthermore, any journalist interested in this issue already has them. Just because they are not being quoted, does not mean that the documents are not widespread.

The truth is, Lilly has been successful in using the court system to threaten and intimidate citizens, including journalists, into silence. After watching the harassment of all the people caught up in this dog-and-pony show, as Lilly causes them to run up massive legal bills, no sane journalist would openly quote from those documents.

Lilly has plenty to lose if the truth comes out and doctors and consumers decide the risks associated with Zyprexa far outweigh the benefits. In 2005, Zyprexa represented 30% of the company’s total sales.

But if Lilly is to be believed that it is not promoting the off-label use of Zyprexa, there seems to be no end in sight to the epidemic of mental illness sweeping the planet because according to Lilly’s latest SEC filing, Zyprexa sales rose another 12% to $1.16 billion in 2006.

Lilly has no one but itself to blame for the mess its in. If the company had ignored the articles in the Times, and went on its merry way of promoting Zyprexa off-label the same way it had for a decade, people would have lost interest in the story and forgotten what was in the documents.

Furthermore, if Lilly is looking for a scapegoat, the finger of blame should be pointed at the company’s high-priced legal team that screwed up royally by opening the door to First Amendment arguments.

Filed under: 2007, antipsychotics, Eli Lilly, Scoop, Zyprexa

Latest Celebrex Court Ruling 50/50

Evelyn Pringle September 18 2006

According to Pfizer, Celebrex is still selling like hot cakes with worldwide sales of $471 million in the second quarter of 2006, representing growth of 17% over the same period last year, with sales in the US of $355 million.

“We continue to expect full-year Celebrex revenues of at least $2 billion, an ambitious target given the ongoing pressures in the arthritis market,” Pfizer told shareholders in its Second Quarter 2006 SEC filing.

Notwithstanding the fact that the FDA asked Pfizer not to run ads to promote more use of Celebrex, and that the company previously granted that request, Pfizer is right back at it. In April 2006, it began advertising Celebrex “in alignment with our new Direct-to-Consumer (DTC) advertising principles, highlighting Celebrex’s unique clinical profile and benefits,” Pfizer wrote in its First Quarter 2006 SEC filing.

Celebrex is a COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) used for pain relief, marketed and sold by Pfizer, Pharmacia, and GD Searle. Over the past several years, these drug makers have been hit by a massive number of lawsuits filed all over the US.

A majority of plaintiffs are represented in class actions. The procedure for filing a class action is to file suit with one or several named plaintiffs on behalf of a putative class which must consist of a group of individuals or entities that have suffered a common wrong.

Several putative class actions have been filed by consumers seeking damages from the purchases of Celebrex as a result of Pfizer’s deceptive marketing scheme. In September 2005, all of the purchase claims, as well as the product liability personal injury actions, were transferred to Judge Charles R Breyer in the US District Court for the Northern District of California, by the Multi-District Litigation Panel, In Re: Bextra and Celebrex Marketing Sales Practices and Product Liability Litigation, MDL Docket No 1699, No 05-1699, (ND CA)

At the plaintiffs’ request, the court allowed the filing of a Purchase Claims Master Celebrex Complaint which includes four claims for relief: (1) RICO; (2) state consumer protection laws; (3) unjust enrichment; and (4) breach of warranty.

The complaint seeks damages on behalf of a national class of all Celebrex End-Payors located in the US, including Consumers and Third-Party Payors who purchased and/or paid for Celebrex not for resale during the period from December 1, 1998 through the present.

The Prescription Access Litigation Project filed a Celebrex class action in California in February 2005, as well as a nationwide case in April 2005, which are included in the MDL proceeding.

PAL plaintiffs allege that, to increase its sales, Pfizer launched a massive deceptive advertising campaign to convince consumers that Celebrex was a premium drug that offered significant benefits over older, cheaper pain relievers. When in fact, PAL alleges, not only did Celebrex offer no safety benefits to the majority of consumers, it actually increased their risk of death from a heart attack or stroke.

According to PAL, in December 2004 and in February 2005, Pfizer disclosed two separate studies showing that Celebrex users have an increased risk of cardiovascular events and that had Pfizer revealed the risks of Celebrex, of which it was aware since 1999, consumers would not have been willing to pay the high price for Celebrex.

PAL alleges that Pfizer convinced consumers to pay a higher price than they would have paid if they had known the risks, if they would have purchased Celebrex at all. The suits seek recovery for consumers who purchased Celebrex at the inflated price made possible only by Pfizer’s massive deceptive advertising campaign.

The plaintiffs specifically allege that the marketing scheme was deceptive because Pfizer (1) suppressed data showing the cardiovascular risks associated with Celebrex; (2) falsely claimed that Celebrex caused fewer gastrointestinal side effects than traditional NSAIDs; and (3) falsely claimed that Celebrex provided superior pain relief and safety over traditional NSAIDs.

The plaintiffs maintain that as a result of the marketing success, Pfizer was able to sell Celebrex “at a premium price over NSAIDs and to have it become a standard treatment option as opposed to use of less expensive NSAIDs.”

According to the lawsuits, Celebrex sells for $2.53 to $6.45 per day, depending upon the dose, while NSAIDs sell for $0.21 to $0 .31 per day.

The plaintiffs allege that if Pfizer had not engaged in the wrongful marketing, advertising and promotion of Celebrex, they would have paid for other equally effective and less expensive medication.

On March 31, 2006, Pfizer filed a motion to dismiss the case. Plaintiffs opposed the motion, and a hearing and status conference was held on June 30, 2006.

In moving to dismiss the failure-to-warn claims, Pfizer argues that the claims are preempted because they conflict with the Food, Drug and Cosmetic Act (“FDCA”) and the authority of the Food and Drug Administration (“FDA”) to regulate warnings about prescription medicine and the promotion of such medicine.

On August 16, 2006, the Court ruled that claims that Pfizer failed to warn about the cardiovascular risks were preempted by the FDA’s authority to determine prescription drug labels, and that those claims were dismissed but with permission for plaintiffs to amend the complaint.

In opposing the motion, the plaintiffs argued that because the FDA’s preemption statement appears in a preamble to a Final Rule, and is not itself a regulation or even an interpretative rule, the Court should ignore the FDA’s view.

The plaintiffs asserted that Congress had not delegated authority to the FDA to opine on the preemptive effect of its regulations. However, the court ruled that Congress has delegated the responsibility for administering the FDCA to the FDA, and that such responsibility implies the authority and expertise to determine which state laws conflict with its regulations.

The plaintiffs asked the court to consider the inconsistency of the FDA’s position when determining what weight to give the current preemption view and highlighted the FDA’s statements in 1998, that its labeling regulations establish minimum standards, and that in 2000, when the FDA published the proposed drug labeling rule to which the preemption preamble is now attached, that the FDA determined that the proposed labeling rule does not preempt state law.

The following year, the plaintiffs argued, only after a change in administrations, did the FDA begin for the first time to submit amicus briefs arguing in favor of preemption.

The court noted the drastic change but said it made no difference. “While the FDA’s current view of the preemptive effect of its labeling regulations is a 180-degree reversal of its prior position,” the Court stated, “the Supreme Court has recognized that an agency’s view of the preemptive effect of its regulations may change over time as the agency gains more experience with the interrelationship between its regulations and state laws.”

“Moreover,” the judge continued, “the Supreme Court has never held that a court may not give weight to an agency’s view of the preemptive effect of its own regulations simply because that agency’s view changed contemporaneously with a change in administration.”

The plaintiffs also unsuccessfully argued that the FDA’s failure to comply with Executive Order 13132, regarding consultation with local officials about a possible conflict with state law should be considered.

The court disregarded plaintiffs’ allegation that Pfizer withheld material cardiovascular risk data from the FDA, saying it “does not change the preemption analysis.” The law is well established that a claim premised on a drug manufacturer’s failure to provide data to the FDA is preempted, the court wrote citing a US Supreme Court case.

“Plaintiffs’ state law failure-to-warn-claims,” the judge said, “conflict with the FDA’s determination of the proper warning and pose an obstacle to the full accomplishment of the objectives of the FDCA.”

In its conclusion, that court stated that, “Plaintiffs’ claims that Pfizer’s promotion of Celebrex was unlawful because it failed to warn of the drug’s cardiovascular risks are preempted because they conflict with the FDA’s determination of what warnings are substantiated by the scientific evidence.”

“Accordingly,” the court ruled, “the failure-to-warn of cardiovascular risk claims are dismissed with leave to amend.”

A point not mentioned that indicates the court’s faith in the FDA’s ability, or inclination, to protect the public against dangerous drugs promoted by profit driven drug makers is misplaced, is the fact that it took the FDA two years to negotiate a label change to warn consumers about Vioxx during which time, the FDA’s own career scientist, Dr David Graham, said tens of thousands of people were needlessly injured or killed.

Legal experts say its difficult to gauge how the California decision will effect other Celebrex cases because different judges in different states can mean different results.

According to attorney, Ted Parr, of the Washington DC firm, Ury & Moskow, “State court judges are likely to reach conclusions regarding preemption that are inconsistent, both with the federal court and with each other to some extent.”

“Some cases will be dismissed, and others will not,” he states.

For instance, he points to the Pennsylvania Paxil case, Colacicco v Apotex, Inc, where the court dismissed the entire lawsuit, since, under Pennsylvania state law, failure-to-warn is the only cause of action available.

On the other hand, in another Pennsylvania case, Mingus v Wyeth, Mr Parr states, “the plaintiff withdrew her failure-to-warn claim and agreed to proceed only on claims for negligence and strict product liability based on design defect under Ohio law; in that case, the court denied the defendant’s preemption motion.”

“We really do not know yet,” he advises, “how extensive the preemption problem will be nationwide.”

“Two federal courts in the 8th Circuit have rejected preemption motions,” he points out.

The fact that studies might come out, like has happened in Vioxx litigation, that show Pfizer knew about the heart risks might not even make a difference, according to Mr Parr.

“The defendants will no doubt argue that the FDA’s enforcement mechanisms are exclusive,” he explains. “Therefore, even if it were shown that Pfizer engaged in outright willful fraud,” he said, “the plaintiffs’ claims could still be dismissed.”

As for whether all Celebrex plaintiffs will be permitted to amend their complaints, the answer is once again a mixed bag. “Some plaintiffs may have an opportunity to amend their claims;” Mr Parr states, “others will not, depending upon the interpretation of preemption and decision of the court and differences in state laws.”

In moving for a dismissal of the GI claims, Pfizer argued that the plaintiffs’ theory of liability, that Pfizer falsely claimed that Celebrex had fewer GI complications than other NSAIDs, and was more effective, was preempted because it stands as an obstacle to the accomplishment of the objectives of the FDCA.

Pfizer maintained that the FDA requires companies to submit all advertising to the
FDA’s Division of Drug Marketing, Advertising, and Communications, and that the
DDMAC reviews the ads for compliance, and has the authority to require a company to stop running a particular ad or to run a corrective promotion.

According to Pfizer, the FDA has “necessarily determined” that the unobjected to ads are accurate and strike a fair balance between the benefits and risks of Celebrex; therefore, any claim that such ads were deceptive conflicts with the FDA’s determination and are impliedly preempted.

The court acknowledged that Pfizer has submitted its challenged ads to DDMAC and, with a few exceptions, the DDMAC did not object to the ads.

However, the judge stated, “there is nothing in the record from which the Court could conclude that the FDA has actually reviewed all of the submitted advertisements, let alone conclude that the FDA’s review means that it has definitively determined that the advertisement was not misleading.”

The court pointed out that the FDA’s silence is significant here because when “the FDA believes that its regulations preempt state law it says so.”

“The FDA has been silent with respect to the preemption of lawsuits challenging false claims in prescription drug advertisements,” the court wrote. “This silence suggests that the FDA does not intend its review of promotional materials to preempt false advertising claims.”

The plaintiffs’ claims are premised on the assertion that the ads imply that Celebrex is superior to other NSAIDs because it has fewer GI symptoms, a claim which the FDA expressly determined would be false and misleading.

Pfizer argues that particular ads identified in the complaint are consistent with the FDA-required label and therefore any claims based on those ads are preempted.

Pfizer is actually arguing, the judge said, that certain ads were not misleading as a matter of law, that the ads do not imply GI superiority or greater efficacy than other NSAIDs.

The court said it declined to make such a determination on the limited record and briefing currently before the Court.

Pfizer also argued that the FDA should initially decide whether the ads are misleading because plaintiffs’ claims fall within the “primary jurisdiction” of the FDA.

The court determined that the false advertising claims do not implicate the primary jurisdiction doctrine. “The issue is not whether Celebrex has fewer GI complications than other over-counter NSAIDs;” the court stated, “the FDA has already determined that it does not.”

“The issue,” it explained, “is whether contrary to the FDA’s findings, Pfizer nonetheless falsely claimed that Celebrex was superior.”

Courts and juries frequently decide similar false advertising claims, the court noted.

In its conclusion, the court stated that, “Pfizer has not established that the FDA has determined that all of Pfizer’s promotional material strikes a “fair balance” and are not false and misleading.”

“Accordingly,” the court ruled, “Pfizer’s motion to dismiss the false advertising claims on conflict preemption grounds is denied.”

There is certainly ample evidence to present to a jury to back up the claims that the Celebrex makers engaged in false advertising and over-promotion of Celebrex, within the walls of the various FDA offices alone.

First off, Pfizer’s claim that Celebrex ads were preapproved by the FDA is dead in the water. On December 1, 2005, Tom Abrams, director of the DDMAC, said in an interview for Pharmaceutical Executive that although FDA regulations require companies to submit advertising material at the time of first use, his office receives an average of 53,000 promotional items a year and his staff of 35 cannot handle that volume of screening.

“DDMAC has limited resources and we use our limited resources as effectively as we can to do our job,” he said.

In fact, Mr Abrams says the biggest misconception is that the FDA approves all ads before they are released, and most ads are launched without the agency reviewing them. In fact he states, “Often, we’re seeing it at the same time as the American public.”

According to Mr Abrams, when the FDA determines that an ad violates regulations, the agency sends the company either a notice of violation letter or a warning letter. Notice letters are issued for the least serious offenses and warning letters are issued for serious or repetitive violations and request that the company stop the promotion, and disseminate corrective messages.

FDA records show that Celebrex received seven citations for false or misleading promotions between 1997 and 2005. In 1997, before Celebrex even obtained FDA approval, the FDA accused Celebrex maker at the time, GD Searle, of touting the drug on the internet as “a breakthrough in arthritis therapy,” and suggesting that it caused no gastrointestinal bleeding.

The claim of no gastrointestinal risks was not approved for the label when the FDA approved Celebrex and yet, Searle, Pharmacia and Pfizer, have each been cited for stating or implying in promotional materials that Celebrex worked better than other pain relief drugs because it posed no gastrointestinal risks.

In fact, when the FDA approved Celebrex it specifically warned that any promotional activities “that make or imply comparative claims about the frequency of clinically serious GI events compared to NSAIDs or specific NSAIDs will be considered false and/or misleading . . .”

Furthermore, the FDA required the Celebrex label to include the warning that “serious gastrointestinal toxicity can occur at any time, with or without warning symptoms, in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs).”

In 2005, the FDA required the Celebrex label to include a boxed warning stating: “NSAIDs, including CELEBREX, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.”

Claims that portray Celebrex as a superior pain reliever are also false and misleading because the FDA has stated that, “none of the comparative studies with naproxen, ibuprofen, and diclofenac to-date has been designed to demonstrate superiority or a specified degree of similarity in a rigorous way.”

One Celebrex TV ad found to be false and misleading promoted the drug for use in treating osteoarthritis or rheumatoid arthritis, and shows a woman playing a guitar with a voice-over saying, “With Celebrex, I will play the long version.” The FDA sent Pfizer a “warning” letter on this ad stating:

“While the Guitar TV ad suggests a direct benefit to this patient’s wrist/hand/finger joints related to movement and flexibility, it fails to state the actual approved indication (e.g., relief of signs and symptoms of osteoarthritis).”

The FDA also pointed out that this ad failed to include any risk information about Celebrex, thus omitting the major side effects and contraindications, and said the omission of this information implies that there are no risks, which overstates the drug’s safety.

The FDA determined that another TV ad was misleading and warranted a warning letter that began with the announcement: “Celebrex presents, arthritis tips.”

The ad features a woman dressed as doctor stating: “Arthritis is the most wide-spread crippling disability in the United States today. Arthritis is the predominant cause of activity limitations and is a major determinate of nursing home institutionalization for the elderly.”

“One out of every 7 people and 1 in every 3 families is affected by arthritis,” the ad states. “If you feel any pain or discomfort in your joints, contact your local doc.”

The commercial concludes by saying: “These arthritis tips have been brought to you by Celebrex.”

The FDA said that this ad is product-specific, and misleading because it omits important information about the drug’s safety and effectiveness and makes unsubstantiated claims. The FDA said the ad promotes Celebrex by name at the beginning and end and that using the term arthritis tips clearly suggests that the drug is an arthritis treatment.

The totality of this presentation, the FDA letter advised, suggests that Celebrex is an effective treatment for preventing or modifying the progression of arthritis, such that crippling disability and nursing home institutionalization may be avoided, when in fact, Celebrex is indicated only for relief of the signs and symptoms of OA and RA and is not indicated for disease modification (i.e., altering the course of the progression of arthritis).

“Moreover,” the FDA said, “we are not aware of substantial evidence or substantial clinical experience demonstrating that treatment with Celebrex will prevent crippling effects or disability due to arthritis or prevent nursing home institutionalization of elderly patients with arthritis.”

“Therefore,” the letter warned, “your Arthritis Tips TV ad greatly overstates the proven benefits of Celebrex.”

The FDA also noted that the ad fails to disclose any risk information and omits the major side effects and contraindications, including warnings and precautions, which implies that there are no risks to the patient who takes Celebrex, thus overstating its safety.

In the same letter the FDA warmed that a Celebrex print advertisement also made unsubstantiated claims with respect to less expensive alternative drugs. The print ad features the headline “Strength They Can Stay With” and shows a chart comparing Celebrex, Ibuprofen and Naproxen, titled “6-Month Patient Persistency Rate.”

Over the chart is the statement, “In a study of approximately 1 million patients, persistency rates of different OA/RA treatments were assessed at 6 months.” The line below the Celebrex logo says, “Proven strength that lasts.”

The FDA said these claims imply that Celebrex is more effective (i.e., stronger) than ibuprofen and naproxen for treatment of osteoarthritis or rheumatoid arthritis and that
patients “stay with” or are more compliant with Celebrex therapy than with the other products. “We are not aware of substantial evidence or substantial clinical experience to support these claims,” the FDA wrote.

The cited retrospective retail pharmacy database analyses by NDC Health, the FDA advised, do not contain any data or information demonstrating that patients found Celebrex to be more effective than the other products, or that patients will be more “persistent” or compliant with Celebrex therapy.

Moreover, the agency said, the information did not note the indication for which the drug was prescribed, so the suggestion that these rates reflect specifically OA/RA patients is misleading.

In addition, the FDA said, the analyses do not account for factors that affect persistence or compliance such as cost insurance coverage, side effects, dosage regimen, and ease of use.

“Therefore,” the agency wrote, “the analyses do not constitute substantial evidence or substantial clinical experience demonstrating that OA/RA patients are more compliant with Celebrex or stay on Celebrex longer because it is more effective than other products for the treatment of OA or RA.”

Experts say these overly aggressive promotional campaigns are causing great harm to consumers. Former FDA commissioner, David Kessler, told the San Francisco Chronicle, February 27, 2005, that the rapid adoption of new drugs — fueled by heavy promotional campaigns — is an inherent threat to the public.

“The way it used to be, if a drug got approval, its use would increase gradually over time,” said Mr Kessler, who is dean of the UCSF School of Medicine. Thus, when unexpected side effects surfaced, he said, relatively few people had been exposed to the risk.

In recent years, though, he said, new medicines explode into widespread use before they build up a safety track record. Mr Kessler is credited with preventing the widespread use of drug TV commercials when he was commissioner.

“Many more people are going to be exposed,” he warned in the Chronicle. “That’s the nightmare.”

Patients who suffer from chronic pain, like Sandy Lambrecht, say Pfizer and other drug companies take advantage of their suffering. “Excruciating relentless pain is indeed a strong motivator,” she states.

“That’s why so many of us finally give in and take drugs that may indeed harm us even further,” she explains, “we are that desperate.”

Sandy says chronic pain sufferers keep up with the news about pain drugs like Celebrex but when the doctor says take it or go without, they take it. “We are not stupid,” she states, “we know that we are being coerced into taking drugs pushed by these unconscionable criminals.”

Her medicine cabinet still has half-empty bottles of Vioxx, Celebrex and Bextra. Last month she found out that she has heart problems, but has no way of knowing if its related to one of those drug or all 3. “And it’s not likely I’ll ever find out,” she says.

“We pay a price that is rarely considered in law suits,” Sandy notes, “and we never get recognition – let alone any compensation – for simply being in such tragic situations.”

Sandy contends that the few dollars still being spent on the disabled should not be used to boost drug companies profits. “I’ve long known that the real criminals are not the few people who take advantage of social programs,” she states, “its the greedy corporations whose legions of unscrupulous lawyers and salesmen exploit the most vulnerable of our society.”

Critics agree that consumers have been ripped off when it comes to Cox-2 inhibitors. “Though billed as super aspirins,” says Merrill Goozner, author of, The $800 Million Dollar Pill, “the Cox-2 inhibitors provided no more pain relief than over-the-counter aspirin, ibuprofen, or prescription naproxen, which were the most popular NSAIDs on the market.”

“This inconvenient fact,” he says, “was overlooked by the new drugs’ marketers.”

In the spring of 2002, then Pfizer CEO, Henry McKinnell, awarded PhRMA’s highest research award to the four scientists who developed Celebrex stating:

“Thanks to their pioneering work, millions of people throughout the world who were once crippled with arthritis can now work, walk, garden, and do all the little things that make life worthwhile.”

Mr McKinnell said all this, even though, as Mr Goozner points out, “they were no more able to perform those tasks than if they had popped a couple of over-the-counter ibuprofen.”

Pfizer has been one of the foremost proponents of the position that many FDA rules limiting drug advertising violate the company’s First Amendment right to free speech. That argument has made headway in a number of court cases, former deputy commissioner, Mary Pendergast, acknowledged to the San Francisco Chronicle on February 7, 2005.

However, according to Ms Pendergast, the FDA could still win a case for promotional limits by producing enough evidence to show public health could be at risk.

“You don’t have a First Amendment right to lie, to say false and misleading things,” she points out.

Filed under: 2006, Celebrex, FDA, NSAIDs, Pfizer, Scoop

Pfizer Celebrex Lawsuits – 1500 and Counting

Evelyn Pringle September 5, 2006

The first Celebrex trial, originally set for June 6, 2006, has been delayed indefinitely, reportedly to give attorneys more time to gather information. Although no new trial date has been set, legal analysts now predict that Celebrex trials will begin in early 2007.

The delay was requested by a federal judge in San Francisco, where Pfizer is facing around 1,500 lawsuits related to its painkillers Celebrex and Bextra, according to Bloomberg News. In light of the studies on Celebrex that have surfaced over the past year, any media update should say 1,500 lawsuits and counting.

The lawsuits filed actually list defendants involved in the development, manufacturing and distributing of Celebrex as Pfizer Inc, Pharmacia Corp, Monsanto Co, and GD Searle & Co.

On August 30, 2006, Health Day News doused Pfizer’s last hope of ever finding a reason to justify the over-prescribing of Celebrex when it reported that the “final word on whether the cox-2 painkiller Celebrex might be used to prevent colon cancer is a definite “no,” according to the long-awaited results of two major studies.”

“Both of the three-year trials found that the drug reduced the occurrence of precancerous polyps called adenomas in people at risk for colon cancer,” Health Day wrote, “but it more than doubled patients’ risk for heart attack and other serious cardiovascular events.”

“The message is that celecoxib has no role as a chemotherapeutic agent — in people with adenomas or in people among the general population,” said Dr Bruce Psaty, a professor of medicine, epidemiology and health services at the University of Washington in Seattle, who co-authored an editorial on the two studies, published in the August 31, 2006, New England Journal of Medicine.

According to Dr Psaty, the take home message is that the cardiovascular risks “far outweighed even the most optimistic projections about the drug’s cancer-prevention properties.”

More bad news was reported a week earlier on August 24, 2006, by MedPage Today, in the results of a Canadian study that found women who take NSAIDs (nonsteroidal anti-inflammatory drugs), such as Celebrex, during the first trimester of pregnancy have twice the risk of having babies with congenital anomalies, particularly cardiac septal defects, researchers reported.

Of 1,056 women who filled prescriptions for NSAIDS during the first trimester of pregnancy, 8.8% had infants with congenital abnormalities, compared with 7% of 35,331 women who did not use NSAIDs, said Anick Berard, PhD, of Sainte-Justine Hospital, and colleagues, in the September 2006, issue of Birth Defects Research Part B.

And a few months ago on March 1, 2006, the Scotsman reported: “In a study involving more than 4,000 patients, Celebrex, which is the most commonly used Cox-2 inhibitor, was found to increase the risk of heart attacks by 2.26 times.”

The leader of the study, Professor Richard Beasley, from the Medical Research Institute of New Zealand, warned that, “Given the popularity of this in the treatment of arthritis, drug regulators must undertake an up-to-date risk assessment based on the findings presented here.”

The study was published in the Journal of the Royal Society of Medicine and reported that in addition to the increased risk when compared to a placebo, the use of Celebrex also had a 1.88-fold increase in the risk of heart attacks when compared with other painkillers.

According to a November 16, 2005, study conducted in Denmark, presented to the American Heart Association, people who have survived a previous heart attack and take Celebrex are at an increased risk of death, especially if they take Celebrex at higher doses.

The lead researcher, Dr Gunnar Gislason, stated that people with heart disease or history of heart attack should not use Celebrex. The study showed that heart disease patients who take 200 mg of Celebrex a day are more than four times more likely to die.

The first Celebrex trial that was delayed involves the case of Rosie Ware, an Alabama woman who alleges that a stroke at age 53, in February 2005, was caused by Celebrex and that the stroke has resulted in medical, hospital, and after-care costs of “substantial sums of money.”

Ms Ware is represented by the law firm of Beasley, Allen, Crow, Methvin, Portis & Miles, in Montgomery, AL. On February 28, 2006, Attorney Jere Beasley told the Wall Street Journal that his client, a nonsmoker whose health was “very good” before her stroke, took Celebrex for back pain and was left disabled and unable to work after the stroke.

Mr Beasley also told the Journal that he is undeterred by the fact that Celebrex has been deemed safe by federal regulatory agencies. “I don’t think that makes much difference,” he said. “The FDA is just an extension of the drug industry.”

Ms Ware alleges in her lawsuit that had it not been for Pfizer’s overly aggressive marketing campaign with misleading claims about the safety and efficacy of Celebrex, she would never have taken it to begin with.

This allegation is pretty much verified by a study published on January 24, 2005, in the Archives of Internal Medicine, titled, “National Trends in Cyclooxygenage-2 Inhibitor Use Since Market Release,” which concludes that the “aggressive marketing techniques to patients and physicians” caused a growth not only in use of COX-2 inhibitors but also in overall market demand, resulting in the use of such drugs by patients who did not need them.

The study in Archives found that 63% of patients who received COX-2 inhibitors were at a low risk for developing the ulcers and gastrointestinal problems that the drugs were supposed to prevent, and that the marketing campaign played a significant role in the over-use of COX-2 inhibitors for this type of patient.

In both the non-risk and at-risk population, the study found, Celebrex was neither more effective or safer than NSAIDs, meaning that there was a small population for which it might be a superior product, but for the vast majority of users, its use was excessive.

According to Merrill Goozner in the new best-selling book, “The $800 Million Pill:”

“Sales exploded the instant the FDA gave the okay for the drugs’ makers to rev up their marketing machines. Commercials featuring frisky seniors flooded the airwaves. Detailers inundated doctors with free samples. Millions of people pestered their physicians to give them prescriptions for the new drugs, requests that fell on receptive ears.”

Mr Goozner states that, “Wall Street’s stock analysts considered the rollouts of Celebrex and Vioxx the most successful drug launches in pharmaceutical industry history.”

“Within a year of its launch,” he notes, “Celebrex was generating more than $2 billion a year in sales for Pharmacia and its comarketer Pfizer.

“Arthritis pain relief medicine that had once cost pennies a day,” he says, “was now costing millions of patients and their insurers nearly three dollars a pill.”

Celebrex in fact, has no proven superiority over other NSAIDs and yet it sells for anywhere between $2.50 to $6.50 per day depending on the dose, while NSAIDs sell for $0.21 to $0.31 per day which means Pfizer has made billions of dollars off Celebrex by charging an outrageous price for a drug that in reality is not even better than over-the-counter drugs that cost pennies per pill and have been on the shelves for years.

Had the truth been known about the drug’s lack of safety and efficacy, critics says, Celebrex would have sold for a price similar to other NSAIDs and would not have become a standard in the treatment of arthritis and other forms of pain relief.

In 2004, Pfizer spent $117 million promoting Celebrex and sales reached $3.4 billion worldwide, according to the April 28, 2006, New York Times. The following year, after advertising of Celebrex ceased, sales dropped 48% to $1.73 billion in 2005, the WSJ reports.

Although scrutiny over marketing practices intensified following the Vioxx recall, violations of advertising regulations have been getting worse, according to Tom Abrams, director of the FDA’s Division of Drug Marketing, Advertising, and Communications, speaking in an interview for Pharmaceutical Executive on December 1, 2005.

FDA regulations require drug companies to submit promotional materials to the FDA at the time of first use which means Mr Abrams and his staff of 35 receive an average of 53,000 promotional pieces a year, he estimates.

He says the biggest public misconception is that the FDA screens and approves all ads before they are released but that most ads are launched without the agency reviewing them first. “We get complaints from consumers and physicians who call us up and say, ‘Tom, how can you allow that TV ad to be on?'” Mr Abrams said during the interview.

“They’re flabbergasted,” he says, “when we say, ‘We didn’t approve it before it went on TV.’ Often, we’re seeing it at the same time as the American public. DDMAC has limited resources and we use our limited resources as effectively as we can to do our job.”

He told Pharmaceutical Executive that competing marketing campaigns within the pharmaceutical industry have become fierce. “Currently, industry spends $25 billion a year on promotion,” he said in the interview.

“I think it is going to continue to increase,” he added.

When the FDA determines that ad is violating regulations, it sends the drug company either a notice of violation letter or a warning letter. Notice of violation letters are untitled and are issued for the least serious offenses. “They pretty much tell companies, ‘Stop what you’re doing and don’t do it again,” says Mr Abrams.

Warning letters, he explains, request that the drug company stop the promotion and disseminate corrective messages, and are issued for more serious or repetitive violations.

Over the years, the misleading and deceptive ads for Celebrex have led to regular correspondence between Pfizer and the FDA.

Since its arrival on the market, Celebrex has been promoted as having the ability to improve the quality of life with ads in which patients go from not being able to work or do much of anything, to being able to work and do everything else pain-free.

In one infomercial, Celebrex patients talk about being able to “do anything,” “do as much as I want to do,” being “back to doing what I do,” and such. They talk about “enjoying life” again, how the drug improved their “quality of life,” and how the drug “gave them back their lives.”

One person states that “you can be free,” and another says that Celebrex “brought new vitality in life.”

Such claims portray Celebrex as a superior pain relief drug when in fact, the FDA has stated that, “none of the comparative studies with naproxen, ibuprofen, and diclofenac to-date has been designed to demonstrate superiority or a specified degree of similarity in a rigorous way.”

Typical of the phony “improve the quality of life” commercials is a TV ad that promotes the use of Celebrex for osteoarthritis or rheumatoid arthritis, with a woman playing a guitar. The visuals focus on her hands and fingers and playing ability with a voice-over saying, “With Celebrex, I will play the long version.”

Combined, the image and voice-over imply that there is a direct benefit to the woman’s wrist, hand, and finger joints so that she can now play the long version and that prior to taking Celebrex she could not.

This misleading ad earned the drug maker the most serious FDA “warning letter” stating: While the Guitar TV ad suggests a direct benefit to this patient’s wrist/hand/finger joints related to movement and flexibility, it fails to state the actual approved indication (e.g., relief of signs and symptoms of osteoarthritis).

It also fails to include any risk information about Celebrex, the FDA said, thus omitting the major side effects and contraindications (including warnings and precautions). Omission of this information, the warning letter said, implies that there are no risks to the patient who takes Celebrex which overstates the drug’s safety.

The Canada’s regulatory agency were also keeping a close watch on Celebrex and apparently so were consumers. On November 4, 2004 a class action lawsuit was filed in Canada alleging that Celebrex caused cardiovascular related side effects and on November 28, 2004, Canada’s Adverse Drug Reaction Monitoring Program confirmed 14 Celebrex related deaths.

About 2 weeks later in mid-December 2004, the announcement came that a clinical trial investigating a new use of Celebrex to prevent colon polyps, conducted by the National Cancer Institute and Pfizer, was discontinued because of an increased risk of cardiovascular events in patients taking Celebrex versus those in the group taking a placebo.

Patients in the trial who were taking 400 mg of Celebrex twice a day were found to have a 3.4 times greater risk of cardiovascular events compared to patients taking a placebo and patients taking the 200 mg dose had a risk that was 2.5 times greater.

The news of this study came a mere 10 weeks after Merck’s recall of Vioxx, when a study found that Vioxx doubled the risk of heart attack and stroke among patients taking the drug to prevent colon polyps.

In fact, on September 30, 2004, in response to Merck’s announcement, Pfizer issued a press release bragging that over 27 million patients in the US had been prescribed Celebrex since it was approved and said people should use it instead of Vioxx.

“Because of its outstanding long-term safety profile and broad indication base including osteoarthritis, rheumatoid arthritis and acute pain, Celebrex is an appropriate treatment alternative,” said Dr Joe Feczko, Pfizer’s president of worldwide development.

The press release claimed that a recent FDA sponsored study of 1.4 million patients, found that those patients who received Celebrex demonstrated no increased risk of cardiac events. “Pfizer is confident in the long-term cardiovascular safety of Celebrex,” Dr Joe Feczko stated.

Well, that glory was short-lived because in January 2005, following a sharp decline in new prescriptions for Celebrex after the December 2004 study was revealed, Pfizer investors filed a federal class action lawsuit against Pfizer in Connecticut alleging that the company misled investors about the safety of Celebrex.

A former Vice President of Pfizer turned whistleblower, Peter Rost, says shareholders were rightfully upset and estimates that the fiasco probably cost Pfizer $3-4 billion.

As for the potential damages to the company from all the lawsuits filed, Mr Rost states companies like Pfizer usually carry some insurance but says, “Most comes out of shareholders pockets.”

He predicts that more hidden studies and documents will pop up during litigation.

And that too seems likely being Pfizer has been forced to acknowledge that a study that was testing Celebrex as a treatment for Alzheimer’s disease between 1997 to 1999, showed patients taking Celebrex quadrupled their risk for a heart attack compared to those patients taking a placebo.

The study found patients on Celebrex had a 3.6 times greater occurrence of a serious heart event compared to those on a placebo, according to an analysis of the data by the patient advocacy group, Public Citizen.

On January 24, 2005, Public Citizen petitioned the FDA to immediately remove Celebrex from the market and a week later on January 31, 2005, Citizen accused Pfizer of burying the study. Sidney Wolfe, director of Public Citizen’s Health Research Group, said “there is no excuse for this study not being made more public.”

Critics say this study proves that the drug makers knew that Celebrex was a total fraud before the drug even hit the shelves.

According to Merrill Goozner, author of the $800 Million Dollar Pill, the only legitimate selling point for the Cox-2 inhibitors was the claim that they would eliminate the ulcers and deaths that on rare occasions resulted from the prolonged use of generic painkillers.

“Yet the FDA didn’t allow them to claim that in their advertising or literature,” he points out, “since the clinical trials failed to turn up evidence that the new drugs were safer than NSAIDs.”

“The package insert, which goes out with every prescription,” he notes, “contained the same warning label as all the other NSAIDs.”

Critics predict that Vioxx, Celebrex and Bextra will go down in history as a shining example of the danger posed by allowing the unbridled promotion of prescription drugs to both doctors and patients.

Experts blame the doctors for over-prescribing and being so gullible to trust the information in promotional materials furnished by drug companies. On June 22, 2000, Dr Marcia Angell, wrote in the New England Journal of Medicine:

“Unfortunately, many doctors do indeed rely on drug-company representatives and promotional materials to learn about new drugs, and much of the public learns from direct-to-consumer advertising. But to rely on the drug companies for unbiased evaluations of their products makes about as much sense as relying on beer companies to teach us about alcoholism. The conflict of interest is obvious.”

“The fact is,” she said, “marketing is meant to sell drugs, and the less important the drug, the more marketing it takes to sell it.”

“Important new drugs do not need much promotion,” she wrote.

Filed under: 2006, Celebrex, NSAIDs, Pfizer, Scoop, whistleblower

SJS – Called A Fate Worse Than Death

Evelyn Pringle January 29, 2006

Until Susie Orme developed Stevens Johnson Syndrome, it was a condition she read about in medical textbooks and a difficult topic to study for on her postgraduate exams. Susie is a doctor and as such, she was able to diagnose her own SJS.

However, “no amount of training could prepare me for the pain ahead,” she said.

Susie’s SJS was a reaction to the anticonvulsant drug lamotrogine. It started with a headache. Susie thought she had the flu and that it would pass and went to bed.

When she awoke her mouth was ulcerated and her eyes had become swollen, blotchy and painful. Within 24 hours her lips had sloughed off and she began to spit rotting flesh and blood from her mouth. Her genitals were swollen and sore and it was agonizing to urinate.

Her overriding memory is one of excruciating pain, Susie recalls, “of feeling that my body was burning and that someone had poured acid into my eyes.” The pain was so extreme that even morphine provided limited relief.

As the SJS progressed, Susie appeared as badly on the outside as she felt on the inside. “I no longer looked like a human being,” she said, “it was terrible for my family to watch me suffer and awful for me to know that the staff who cared so well for me were also physically shocked and repulsed when they saw me.”

“I felt utterly beaten by this awful disease,” Susie recalls. “Each time I closed my eyes the eyelids stuck together and had to be painstakingly bathed apart by the nurses,” she said. Her eyes hurt so badly and her vision became so poor that Susie remembers fearing for her eye sight more than death.

A year has now passed since she acquired SJS, and Susie says that she is recovering but has not yet recovered.

Even after the acute SJS phase is over, its after effects can last a lifetime. For instance, the nailbeds on Susie’s hands are permanently damaged.

She continues to get corneal abrasions due to in-growing eyelashes and her eyes are still very bothered by bright light. Susie’s tear ducts have been permanently damaged and she says, “using artificial tears has become as routine as breathing.”

Overall Susie remains optimistic. “By some miracle considering the severity of my illness,” she notes, “I can see and if I wear sunglasses can manage to do most things without too much pain.”

“My face looks unfamiliar due to the scarring of my eyelids,” Susie said, “but does not look as disfigured as I envisaged it might.” There is scarring on her genitals and initially it was difficult to have sex but with patience this problem is now better, she says.

“At the start of this terrible disease it feels as if there is no hope,” Susie recalls. But she wants other people with SJS to know that there is hope and that with time, patience, and determination, they too “can overcome this terrible illness and its consequences.”

Adverse reactions to prescription and over-the-counter drugs are one of the leading causes of death in the United States. Yet, because there is no mandatory reporting system for post marketing adverse affects, less than one percent of events are ever reported to the FDA.

For this reason, no one can provide an accurate number of the cases of Stevens Johnson Syndrome in the US. Described in many drug package inserts as a “serious skin condition,” SJS is in most cases a devastating allergic reaction to a drug and has been described as “a fate worse than death.”

According to experts, SJS causes the immune system to turn on itself to rid itself of the offending drug, in effect burning the patient from the inside out. SJS often causes blindness and results in death in 10 to 30% of the cases.

SJS is characterized by an extremely painful blistering skin rash, peeling skin, and blistering sores in the mucous membranes including the mouth, throat, eyes, nostrils, and anal and genital areas. In the most severe forms of the disease, the skin peels off in sheets from large areas of the body, much like with severe burn injuries.

Although SJS continues to be listed as a rare condition and is virtually unheard of by most people, it is becoming much more common. The February 15, 2005 Pittsburgh Post-Gazette, reported that there are between 600-2,000 cases in the US each year.

With more than 40 percent of Americans taking at least one prescription drug (2004 CDC report), the potential for the deadly adverse drug reaction is increasing, according to a SJS Foundation warning in the December 13, 2004 Business Wire.

The Stevens Johnson Foundation was founded as a resource for SJS victims and their families. Its mission is to provide support services, and compile and distribute information about SJS to the public and medical professionals. It also works to promote awareness of the symptoms of SJS so that a quick diagnosis can be made.

“SJS is not as rare as we are led to believe,” said Jean McCawley-Farrell, president of the Foundation. “As prescription drug use increases, we are being contacted by increasing numbers of people,” she adds.

“During the winter months,” Jean reports, “we learn of 15 new cases a week, and that’s only people with Internet access.”

Experts agree that recognition of early symptoms followed by prompt medical attention is crucial in minimizing the long-term effects of SJS. Symptoms include:

Rash, blisters, or red splotches on skin
Persistent fever
Blisters in mouth, eyes, ears, nose, genital area
Swelling of eyelids, red eyes
Conjunctivitis
Flu-like symptoms
Recent history of having taken a prescription or over-the-counter medication

Dr Bernard Cohen, MD, of John Hopkins Hospital, is a pediatric dermatologist and advisor to the SJS Foundation, and says, “typically, the reaction begins within the first two weeks of taking the drug.”

Experts usually distinguish between three forms of the disease Dr Cohen explains, “a milder form called Erythema Multiforme Minor, or EM, Stevens Johnson Syndrome, SJS, and TENS, or Toxic Epidermal Necrolysis Syndrome, the most severe form.”

“With EM, which can be recurrent, there will be lesions on the distal extremities [lower legs and arms] and in the mouth; there is little mucous membrane involvement, however.

“With SJS, which is usually not recurrent, there are usually blistering ulcerations of the cornea, mouth, rectum, genitalia, skin, and urethra, usually accompanied by a high fever and generalized weakness.

“TENS involves the entire skin and mucous membrane; the skin literally sloughs off of the person’s body.”

Dr Cohen advises. “Care must be taken to prevent staph infections of the skin from taking hold,” he said. “Intravenous fluids to prevent dehydration are a must, as the person is usually unable to eat or drink due to the mouth blisters,” he notes.

Some of the lasting complications of SJS that have been reported include blindness, dry-eye syndrome, arthritis, lung damage, asthma, photophobia, chronic obstructive pulmonary disease, loss of nail beds, scarring of the esophagus and other mucous membranes, and chronic fatigue syndrome.

As a physician, Susie Orme says she tells anyone who will listen about SJS. “If I prevent one of my colleagues from writing an unnecessary script and prevent one case of SJS it will have been worthwhile,” she notes.

The most frequently implicated drugs with SJS are antibiotics, anti-convulsants, and non-steroidal anti-inflammatory medications. SJS can be caused by these types of drugs:

painkillers
rheumatoid arthritis
antibiotics
drugs for bi-polar disorder
non-steroid anti-inflammatory drugs (NSAIDS)
barbiturates
anticonvulsants
sulfa antibiotics
penicillins

SJS has been reported as caused by these specific medications

Bextra
Arava
Remicade
Ibuprofen
Daypro
Children’s Motrin
Advil
Topamax
Lamictal
Allopurinol
Phenytoin
Carbamazepine

Why certain drugs cause SJS is still not fully understood. However, it is generally accepted that patients with known allergies to sulfa-based drugs have a greater chance of acquiring the conditions. Examples of sulfa-based antibiotics include:

Penicillins
Tetracycline
Doxycycline
Amoxicillin
Ampicillin
Zithromax/azithromycin
Beta-Lactams
Ciprofloxacin

Proper labeling of drugs is crucial to helping medical professionals and consumers recognize and understand adverse reactions such as SJS. Too often, drugs have sulfa components, but are not labeled as sulfa drugs.

Back on December 9, 2004, the FDA ordered new warnings for Pfizer’s Bextra. The warning identified Bextra as containing sulfa, and said that patients taking the drug had reported serious, potentially fatal skin reactions.

As of November 2004, the FDA had received reports of 87 cases of severe skin reactions in association with Bextra. Twenty of the cases involved patients with a known allergy to sulfa and four of the patients died.

The agency noted that Cox-2 inhibitors, such as Celebrex, and other anti-inflammatory drugs, such as naproxen and ibuprofen, also had a risk for serious skin reactions, but said that the reported rate of the side effect was greater with Bextra.

The FDA also told Pfizer to notify doctors of the risk. On October 15, 2004, Pfizer sent a letter to physicians informing them of the SJS risks associated with Bextra and advised that the skin reaction had lead to hospitalizations and deaths.

Five months later, on April 7, 2005, in a startling move, the FDA went against its own advisory committee’s recommendation to allow Bextra to remain on the market and told Pfizer to remove it, in large part due to its associated risks of SJS.

In addition, the agency ordered Black Box warnings about the risk of SJS on over-the-counter NSAID drugs, such as children’s Motrin and Advil. The FDA’s decision to mandate the strongest warning a label can carry, followed two pediatric cases of SJS where one 9-year-old child died, and another 7-year-old girl became blind after using over-the-counter NSAIDs.

Medical professionals advise patients who have suffered a drug-related case of SJS to avoid the offending drug, and all other drugs in the same class. They also recommend that immediate relatives of SJS victims avoid the same drugs as hypersensitivity has been known to be genetically linked.

Filed under: 2006, Bextra, NSAIDs, Scoop, SJS

Risk Of Harm From Motrin Aleve Advil – Better Odds In Crap Shoot

Evelyn Pringle July 1, 2006

Complications from non-steroidal anti-inflammatory drugs, or NSAID, have been linked to 103,000 hospitalizations and more than 16,000 deaths per year in the US, according to a study published in the American Journal of Therapeutics.

A lack of information, experts say, is the root cause of the lack of concern over the health risks associated with NSAIDs. A report in the January 16, 2005, Science Daily said: “More people die each year from NSAIDs-related complications than from AIDS and cervical cancer in the United States.”

Experts say the risk of their many adverse effects increase and vary depending on the patient’s age, dosage, and duration of use. NSAIDs include:

Ibuprofen (Advil, Motrin, Nuprin).
Naproxen (Aleve, Naprosyn).
Indomethacin (Indocin).
Ketoprofen (Orudis).
Piroxicam (Feldene).

A January 2003, Over-the-Counter Pain Medication Study, by the National Consumer League, determined that NSAIDs make up the largest share of the OTC pain medication market. About 110 million Americans who take OTC pain medications take NSAIDs most often. In fact, the study found, Americans are twice as likely to take NSAIDs than they are to take acetaminophen-based products including Tylenol.

There are also many OTC products that contain ibuprofen such as: Advil Cold And Sinus, Advil Cold, Advil Allergy Sinus, Children’s Advil Allergy Sinus, Ibuprohm Cold and Sinus, Sine-Aid IB, Children’s Motrin Cold.

Products that contain naproxen include Aleve, Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, and Naprapac (copackaged with lansoprazole)

A study published in the June 27, 2006, journal, Circulation, was the fifth study in a little over a year to claim that NSAIDs cause heart problems. The researchers in Circulation say NSAIDs can greatly and quickly increase the risk of death in persons who have already had one heart attack.

Dr Gunnar Gislason, from the Gentofte University Hospital in Hellerup Denmark, and colleagues gathered the medical records from the Danish National Patient Registry on 58,432 patients 30 and older who had survived a heart attack between 1994 and 2002.

They then examined the Danish Registry of Medicinal Product Statistics for information regarding prescriptions of NSAIDs, their dosages, and how long they were prescribed.

With high daily doses of NSAIDs, the study found the likelihood of dying was doubled or quadrupled depending on the specific drug, and the risk of another heart attack went up 22% to 89%.

“In addition,” Dr Gislason told Heartwire on June 21, 2006, ”the average time of treatment in our study was just one month, so it appears that even short courses of these drugs are dangerous in patients with known heart disease.”

“This is not just a problem associated with chronic treatment,” he said.

The study found any use of ibuprofen upped the risk of death by 1.5-fold, and high doses (over 1,200 milligrams a day) increased the risk by 2.2-fold. Diclofenac increased the death risk by 2.4-fold, and at high doses the increase was 4.4-fold.

Experts advise that these risks are not small for heart attack survivors. They amount to one patient harmed for every 24 patients who took diclofenac, and one in every 45 patients who took ibuprofen.

A year ago in June 2005, a British study of more than 9000 people who had suffered a previous heart attack found NSAIDs increased the risk of another heart attack by between 24% to 55%.

In that study published in the June 2005, British Medical Journal, researchers at the University of Nottingham identified 9,218 patients across England, Scotland and Wales, who had suffered a heart attack for the first time, over a specific 4-year period, with ages ranging from 25 to 100.

The researchers examined the prescribing patterns, and took into account other risk factors such as age, smoking habits, and obesity, and found that for patients prescribed the drugs in the three month immediately before the heart attack, the risk increased when compared to patients who had not taken the drugs. With ibuprofen, the risk increased by 24% and with diclofenac the risk increased by 55%.

According to the researchers, given the high prevalence of the use of the drugs by elderly people with an increased risk of heart attack due to age, the findings have considerable implications for public health.

Enough “concerns exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs“, they said.

In the May 23, 2006 online version of the journal, Heart, researchers reported that taking NSAIDs could increase the risk of heart failure among the elderly by almost a third.

For this study, researchers from the Spanish Centre for Pharmacoepidemiologic Research in Madrid reviewed the medical records of 228,660 patients beginning on January 1, 1997, and followed the patients until the end of 2000.

Dr Consuelo Huerta and colleagues compared NSAID use among 1,396 patients between the ages of 60 and 84, who were hospitalized for non-fatal heart failure and a random sample of 5,000 subjects.

Of the patients admitted to the hospital, 14% were on NSAIDs at the time of their admission compared to 10% of randomly selected patients. Over half of those admitted to the hospital were in the age group of 70 to 79.

The research team determined that taking NSAIDs increases the risk of getting heart failure by 30%, after other factors are taken into consideration. The results mean that for every 1,000 people aged 60 to 84, taking NSAIDs leads to one extra hospital admission.

But according to the researchers, the number could rise to 3 among older patients with other health problems such as diabetes, high blood pressure or kidney failure. “Even a small increase in the risk can translate into a significant disease burden in the general population,” the researchers noted.

They point out that their findings are compatible with those of other studies indicating that NSAIDs aggravate heart failure symptoms, leading to more hospitalization for susceptible patients, such as those with a history of cardiovascular disease or a previous heart failure.

And finally, on June 3, 2006, researchers in another study from the Clinical Trial Service Unit at the University of Oxford, together with colleagues from the University of Rome, published in the British Medical Journal, determined that ibuprofen doubles the risk of a heart attack in patients who take it at high doses over a long period of time.

The study is reportedly the largest and most definitive of its kind into the effect of NSAIDs on the heart, and involves 138 trials covering 140,000 patients. The study combined the results of all trials in order to provide the most reliable estimate of the increased risk.

Two NSAIDs – ibuprofen and the prescription-only diclofenac – increased the risk of a heart attack by almost as much as the Coxib drugs like as Vioxx.

The researchers noted that most of the patients did not have pre-existing heart disease and the increased risk amounted to three extra heart attacks in every 1,000 people taking ibuprofen or diclofenac every year. Overall they increased the risk of any vascular event – heart attack or stroke – by 40%.

Experts says the growing body of evidence indicating the certainty of heart problems caused by the use of these drugs is particularly disturbing, because their use has drastically increased since Vioxx and Bextra were withdrawn from the market.

There are also a host of other serious health problems associated with taking NSAIDs that include kidney, liver, and stomach problems, particularly stomach bleeding and ulcers, and high blood pressure.

According to a study published January 3, 2005, in the American Gastroenterological Association journal Clinical Gastroenterology and Hepatology, chronic users of NSAIDs have an increased risk of bleeding and visible damage to their small intestine.

The study analyzed 43 relatively healthy patients, who used NSAIDs daily for relief of pain associated with rheumatoid arthritis, osteoarthritis, or non-specific arthritis, and a control group who did not use NSAIDs or aspirin for their arthritis symptoms.

Results show that 71% of those exposed to NSAIDs for more than 90 days had visible injury to their small intestine ranging from small erosions to severe ulcers.

“We have always known that NSAIDs can cause potentially deadly stomach complications, but the extent of the impact on the small intestine was largely unknown until now,” Dr David Graham, MD, lead author of the study told Science Daily.

According to Dr Thomas Stuttaford, in the May 26, 2006, UK Times Online, the hazards of NSAIDs “causing an exacerbation of indigestion and the gastro-intestinal complications associated with it, such as gastro-intestinal bleeding and even perforation, are well known.”

“Care is needed,” he warned, “when prescribing these drugs for patients over 65, especially if there is any history of peptic ulceration, whether gastric or duodenal, or of chronic indigestion.”

In May 2005, Web MD reported that “for people with high blood pressure, some types of nonsteroidal anti-inflammatory drugs (NSAIDs) can be risky.”

People with high blood pressure are at special risk, according to Web MD, because some of the NSAIDs reduce the blood flow to the kidneys, which filter the blood, causing them to work more slowly which causes fluid to build up in the body. As a result, the increased fluid drives up blood pressure.

In addition, if taken often enough and at a high enough dose, the Web MD article warned, “they can seriously damage the kidneys.”

“People with high blood pressure don’t know the risks of taking some of these painkillers,” Dr Nieca Goldberg, MD, a cardiologist and spokesperson for the American Heart Association told WebMD.

“They assume that anything you can buy over the counter is safe,” he said. “But these drugs are chemicals that can cause side effects.”

“When I have patients with heart disease that suddenly gets much worse,” he advised, “the first thing I ask them is if they’ve used an over-the-counter pain medicine.”

In August 2005, research published in Hypertension: Journal of the American Heart Association warned that women who consume higher doses of non-aspirin painkillers were much more likely to develop high blood pressure than women who do not use the medications.

The study was conducted to determine whether higher doses of pain relief drugs, specifically acetaminophen, NSAIDs, and aspirin, increase a woman’s risk of developing new-onset high blood pressure.

“Because high blood pressure is among the most important causes of death and disease in the United States, and analgesics are the most frequently used medications, a relationship between the two would be important from a public health standpoint,” said lead author John Forman, MD, instructor in medicine, Harvard Medical School, and associate physician, renal division, Brigham and Women’s Hospital, Boston, MA.

Researchers studied 1,903 women ages 51-77, and 3,220 women ages 34-53, who did not have high blood pressure when the studies began. They recorded information about whether the women used pain relief drugs, which type, at what dosage, and for what use, and then tracked whether the women developed high blood pressure. The NSAIDs taken were mostly ibuprofen and naproxen.

The study found that older women ages 51-77, who used an average of 400 mg of NSAIDs (2 ibuprofin tablets) or more per day were about 78% more likely to develop high blood pressure compared to older women who did not use the drugs.

Younger women ages 34-53, who used more than 400 mg a day of NSAIDs, were found to have a 60% higher chance of developing high blood pressure.

The risk of developing high blood pressure for women not taking any of the painkillers was only about 1 to 3% a year, researchers found.

The most surprising finding was the development of high blood pressure in women taking acetaminophen (Tylenol). Women ages 51-77 who took an average daily dose of more than 500 milligrams (one extra-strength Tylenol), had a 93% higher risk of developing high blood pressure within about 3 years. Among women 34-53 who took an average of more than 500 mg a day had a 99% higher risk, the study found.

The results of this study held up even when researchers excluded women who were taking pills for headaches, something that could itself be a result of very high blood pressure, said Dr Gary Curhan, one of the study’s authors from Harvard Medical School.

In May 2005, Web MD warned all people with high blood pressure not to use ibuprofen or naproxen, unless a doctor explicitly said they could. The drugs, Web MD advised, “can also impair the effectiveness of common blood pressure medicines like ace inhibitors (such as Lotensin, Capoten, and Vasotec) and beta blockers (such as Coreg, Lopressor, and Corgard.)”

But as it turns out, this is nothing new. According to Dr Stuttaford, in the May 26, 2006, Times Online: “Research carried out well over twenty years ago showed that the NSAIDs also had a tendency to increase blood pressure.”

“This tendency,” he said, “was more likely to be evident in those patients who had been treated with medication to reduce blood pressure.”

In addition, a 2005 study reported in High Blood Connection, found that NSAIDs also increase the risk for kidney failure, and that the risk is significantly greater for patients with hypertension.

Patients who took diuretics along with NSAIDs, the study found, had 11.6 times the risk of developing acute kidney failure compared to non-NSAID users. The relative risk for calcium channel blockers and NSAIDs was 7.8. The researchers warned that NSAIDs should be used with caution in patients with hypertension or heart failure.

Because there is no mandatory reporting system for post marketing adverse affects for drugs, only between 1% and 10% of all adverse reactions to medications are ever reported to the FDA, which means the actual number of patients harmed by NSAIDs is impossible to determine.

For this reason, the accurate number of cases of Stevens Johnson Syndrome caused by NSAIDs in the US are unavailable. Described in many package inserts as a “serious skin condition,” SJS is a devastating allergic reaction to a drug described by some as “a fate worse than death.”

SJS is characterized by an extremely painful skin rash and blistering sores in the mouth, throat, nostrils, eyes, and anal and genital areas. In the most serious cases, a patient’s skin peels off in sheets from large areas of the body, much like what happens to severe burn patients.

According to experts, SJS causes the immune system to turn on itself to rid the body of the offending drug, in effect burning the patient from the inside out. SJS results in death in 10 to 30% of the cases.

Although SJS was once a rare condition, it is becoming far more common. According to the February 15, 2005 Pittsburgh Post-Gazette, there are now between 600-2,000 new cases in the US each year.

Some of the lasting effects of SJS include blindness, dry-eye syndrome, arthritis, lung damage, asthma, photophobia, chronic obstructive pulmonary disease, loss of nail beds, scarring of the esophagus and other mucous membranes, and chronic fatigue syndrome.

Over a year ago, on April 7, 2005, the FDA asked manufacturers of OTC NSAIDs to revise their labeling to include more specific information to assist consumers in the safe use of the drugs.

“This includes,” the FDA said, “instructions about which patients should seek the advice of a physician before using these drugs, stronger reminders about limiting the dose and duration of treatment in accordance with the package instructions unless otherwise advised by a physician, and a warning about potential skin reactions.”

In the new labeling, the FDA instructed manufacturers to include: (1) more specific information about the potential CV and GI risks; (2) instructions about which patients should seek the advice of a physician before using these drugs; (3) stronger reminders about limiting the dose and duration of treatment in accordance with the package instructions unless otherwise advised by a physician; and (4) a warning about potential skin reactions.

In addition, the agency ordered Black Box warnings about the risk of SJS on all OTC NSAIDs. The FDA’s decision to add the strongest warning label available, followed two pediatric cases of SJS where one 9-year-old child died, and another 7-year-old became blind after using OTC NSAIDs.

Although experts are now saying to cut back on NSAIDs, on June 14, 2006, Wyeth began hawking its new product, Advil PM, promoting its use to battle sleeplessness “a few nights a week or more.”

According to the company’s press release, a survey conducted by the National Sleep Foundation found that almost 20% of Americans (42 million) experienced nighttime pain or physical discomfort that disrupted their sleep a few nights a week or more. In fact, it said, 68% of Americans currently are getting less than eight hours of sleep on weeknights, while the US Department of Health and Human Services recommends at least eight hours of uninterrupted sleep.

The profits up for grabs are as always obscene. According to Wyeth, 15% of Americans are turning to sleep aids, making the sleep aid market a $3.1 billion business annually in the US, of which more than $260 million can be attributed to OTC drugs.

Filed under: 2006, NSAIDs, Scoop, SJS

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