Lawsuit Reveals Serious Safety Problems with the Nonsteroidal Anti-inflammatory Drug Valdecoxib (BEXTRA)

Public Citizen filed suit in the District Court for the District of Columbia on February 25, 2004 against the Food and Drug Administration (FDA) asking that they make public complete copies of the agency’s scientific reviews of the nonsteroidal anti-inflammatory drug (NSAID) valdecoxib (BEXTRA). As a result of this litigation, documentation from these FDA reviews has come to light associating valdecoxib and its injectable counterpart, paracoxib, with serious safety problems.

Valdecoxib was approved by the FDA in November 2001 for the management of dysmenorrhea (painful menses) and osteo- and rheumatoid arthritis, but failed to gain approval for the management of acute pain. The FDA reviews reveal that safety, not effectiveness, was the reason the drug was not approved for acute pain.

Valdecoxib, along with the NSAIDs celecoxib (CELEBREX) and rofecoxib (VIOXX), are called COX-2 inhibitors. In theory, they selectively inhibit the enzyme cyclooxygenase-2 (hence the shorthand name COX-2), and thereby relieve the symptoms of pain and osteo- and rheumatoid arthritis, without causing the perforations, ulcers, and bleeding that are such serious adverse effects of the NSAIDs. In fact, all of the NSAIDs, including the COX-2 NSAIDs, carry essentially the same FDA-required warning about the risk of perforations, ulcers, and bleeding that is in the box above.

The drug is co-marketed by Pfizer and Pharmacia & Upjohn in the U.S. Approximately 8 million prescriptions were dispensed for the drug in 2003 in this country, with sales totaling more than $900 million.

We listed valdecoxib as a DO NOT USE drug in the 2002 Companion to the 1999 edition of Worst Pills, Best Pills. Our initial supposition, without having access to the complete FDA reviews, was that valdecoxib failed to receive approval for acute pain because of lack of effectiveness. We thought this because celecoxib (CELEBREX), another top selling NSAID, initially was not granted FDA approval for the management of acute pain on the grounds that it lacked effectiveness. Celecoxib subsequently has been approved for acute pain.

Since 1998 the FDA has made a practice of posting a complete set of reviews for a new drug on the Internet without the public having to make a formal request (using the Freedom of Information Act) for this information. We routinely study these publicly available reviews. When the FDA posted the documents for valdecoxib, they removed (redacted) all of the agency’s analyses regarding acute pain. The FDA’s explanation for this information’s removal was that it is considered to be confidential commercial information and not disclosable to the public under the Freedom of Information Act. We complained to the FDA that the information about acute pain could not be considered confidential information, as the manufacturer had announced in a press release in March 2001 that it was seeking approval for valdecoxib for this use. The agency was sympathetic but still did not give us the information we wanted.

The oral form of valdecoxib was to be the second prong of a two-pronged marketing strategy that would begin with paracoxib, the injectable form of the drug, that breaks down rapidly in the body to valdecoxib. The plan was to have both an injectable and an oral painkiller so physicians could seamlessly prescribe the same drug prior to surgery and upon a patient’s discharge from the hospital.

In October 2000, the manufacturer submitted its application for the approval of paracoxib for the management of acute pain to the FDA. The FDA informed the company in July 2001 that paracoxib was “not approvable.” The company did not reveal why the application for paracoxib had been rejected.

FDA approval of specific uses, such as acute pain, are important for the economic success of new drugs because legally, a drug company can promote its products only for those uses which are FDA-approved. In this case, however, the manufacturer’s failure to gain approval for acute pain from the FDA did not stop them from promoting valdecoxib for the management of acute pain. This promotion leaves in question whether or not the peer reviewed medical literature can always be relied upon as an objective source of drug information.

While we were unsuccessfully urging the FDA to release their safety and effectiveness reviews of valdecoxib for the treatment of acute pain, the drug’s manufacturer was making an end run around the FDA’s approval process. A press release was issued announcing the publication of studies in the May 2002 issue of the Journal of the American Dental Association (JADA) concluding effectiveness for valdecoxib in the treatment of acute pain associated with dental surgery. This was unusual in itself, as we could not ever recall seeing a press release announcing the publication of drug studies for dental pain in a dental journal.

The JADA publication was co-sponsored by Pfizer and Pharmacia & Upjohn. The studies were conducted by Scirex, a contract research organization, (CRO) which, at the time, was owned partly by Omnicom, one of the world’s largest advertising companies.

Three of the five authors were employees of Pharmacia & Upjohn: the corporation’s Director of Biostatistics, Director of Medical Development, and the Clinical Vice President of Medical Development. These three company officials certainly must have known that valdecoxib failed to gain FDA approval for acute pain, as the two studies published in JADA had been submitted to the FDA in the attempt to gain approval for the drug for acute pain.

According to a New York Times investigation published November 22, 2002 the JADA study “... helped light a fire under Bextra.” Sales of the drug were reported to have increased 60 percent in the three months following the publication of the article. No matter how it is sliced, this company-sponsored study was a misleading commercial communication — an advertisement— and a perversion of ethical scientific communication.

The New York Times also reported that editors at JADA said the Pfizer and Pharmacia & Upjohn article was reviewed by at least three scientists. One reviewer, an associate editor of the journal, said the study was ‘’carefully designed and rigorously performed.’’ But, he also said he would have recommended that the journal reject the paper had he known that valdecoxib was not approved for acute pain.

The Unredacted FDA Review Of Valdecoxib

The FDA had originally redacted all information in their reviews concerning valdecoxib and acute pain. In the course of our litigation, we received most of what we had requested in the lawsuit, including the unredacted FDA Medical Officer’s conclusions and recommendations about the use of the drug for acute pain.

In the unredacted review the Medical Officer recommended:

Nonapproval of the acute pain, including opioid-sparing and prevention of operative pain. The only substantial multidose safety database is found in the Coronary Artery Bypass Graft (CABG) Surgery study 035. This study demonstrated an excess of serious adverse events including death in association with the use of paracoxib and valdecoxib 40 mg bid [twice daily] when added to ad lib [as needed] parenteral [injectable] narcotic analgesia.... These finding[s] warrants further investigation before valdecoxib can be considered safe and effective for the treatment of pain, particularly multidose therapy in the perioperative setting.

In study 035, the CABG study, there was an excess of clinically relevant adverse events in patients receiving valdecoxib and its injectable form paracoxib. There were 80 clinically relevant adverse events occurring in the 311 patients receiving paracoxib and valdecoxib (25.7%), compared with 23 (15.2%) in the 151 patients receiving the placebo.

The results of study 035 were ultimately published in The Journal of Thoracic and Cardiovascular Surgery in June 2003. This was 19 months after the FDA Medical Officer’s review was written. This study generated little fanfare in the general media, certainly nothing to match the coverage of the JADA article published in May 2002.

In the Summary of Clinical Findings section of his review the Medical Officer concluded:

e) No efficacy advantage was demonstrated or suggested for valdecoxib compared to:

i. ibuprofen [MOTRIN], naproxen [ALEVE], and acetaminophen with oxycodone [TYLOX] in analgesesic studies

ii. naproxen, ibuprofen or diclofenac [VOLTAREN] in osteoarthritis studies

iii. naproxen in rheumatoid arthritis studies

In summarizing the safety of valdecoxib the Medical Officer stated:

With two notable exceptions — edema [swelling] and hypertension — valdecoxib was comparable to the standard non-steroidal agents [ibuprofen, naproxen, diclofenac] used as active controls in the trials.... The finding of a greater incidence of edema and hypertension at doses above 20 mg/day, almost uniformly in the databases and clearly when prospectively addressed in formal safety Trials 47 and 62, is of concern.... The excess of serious cardiovascular thromboembolic [blood clots] in the valdecoxib arm of the CABG [Coronary Artery Bypass Graft] trial is of note as the entire study population received prophylactic low dose aspirin as part of the standard of care in this setting to minimize just such events. Given the emerging concern over a possible pro-thrombotic action of certain agents in the COX2 class, these data are of concern.

Valdecoxib is no better, and in some respects more dangerous, than drugs already on the market, including ibuprofen and naproxen which are available over-the-counter in non-prescription strengths.

The amount of money being wasted on valdecoxib is extraordinary with the biggest burden falling on those patients who must pay out-of-pocket for their drugs.

A 20 milligram per day dose of valdecoxib was compared to naproxen given in a dose of 500 milligrams twice daily in osteoarthritis trials. Using prices posted on the Internet from a Washington, DC chain pharmacy, the cost of a 30 day supply of valdecoxib is $98.99. For a 30 day supply of naproxen, a patient would pay only $18.19. This is a difference of $80.80 per month or $969.60 per year.

What You Can Do

You should not use valdecoxib. It is no more effective than older NSAIDs such as naproxen, ibuprofen or diclofenac and it is much more expensive.