Vioxx Study & Information Withheld:

• Expression of Concern: Bombardier et al., “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis,” N Engl J Med 2000;343:1520-8. (PDF). Thursday, December 8, 2005. The New England Journal of Medicine.
• Bombardier, et al. for The VIGOR Study Group. Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis. Friday, November 23, 2000. The New England Journal of Medicine.
• Merck responds to medical publication. Friday, December 9, 2005. CNNMoney.com
• Merck & Co., Inc. Response to an Editorial Posted on the New England Journal of Medicine Web Site. (Press Release). Thursday, December 8, 2005. Merck.com.

Have a Vioxx legal claim? For a free, confidential legal consultation, Submit your Vioxx injury claim or call 1-800-471-3980 now.

Of Note:

• Actual damages: $24.4 Million
• Punitive Damages: $229 Million
• $229 Million is the amount Merck made in sales of Vioxx from Oct. 2001, when FDA suggested the label change, to the February 2002 change.

After two days of deliberation, a Texas jury awarded $24.4 million in actual damages and $229 million in punitive damages to the family of Robert Ernst, who died of a heart attack in 2001 after taking the painkiller and arthritis drug, Vioxx. The amount of punitive damages, $229 million, is the equivalent amount Vioxx maker Merck & Co. made on the drug in the four months between October 2001 and February 2002, the time between an FDA request to add a warning of cardiovascular events to Vioxx’s labeling and Merck’s addition of the warning. The request came as a result of a 2000 study that showed Vioxx users suffered five times as many heart attacks as those who took the older painkiller, naproxen.

Vioxx Lawsuit Articles

• Vioxx jury finds Merck liable. Friday, August 19, 2005. Houston Chronical.
• Jury Finds Merck Liable in Vioxx Death and Awards $253 Million. Friday, August 19, 2005. The New York Times.
• Merck Is Found Liable for Man’s Death in Vioxx Trial. Friday, August 19, 2005. Bloomberg.com.

The VIGOR publication, which was peer-reviewed, fairly and accurately described the results of the study as of the pre-specified cutoff for analysis. The additional events referred to in the editorial were events that were reported after the pre-specified cut-off date and therefore were not included in the primary analysis reported in the New England Journal article. Nevertheless, these additional events were disclosed to the FDA in 2000, presented publicly at the FDA’s Advisory Committee in February 2001, included in numerous press releases subsequently issued by Merck, disclosed to physicians given a copy of the article by Merck and detailed in the updated prescribing information for VIOXX. We also note that these additional events did not materially change any of the conclusions in the article.

Merck is confident in its research. In the research that served as the basis of FDA approval, Merck conducted studies with almost 10,000 patients. Those studies showed similar rates of thrombotic events like heart attacks and strokes between VIOXX and placebo or VIOXX and the comparator NSAIDs like ibuprofen.

Finally, Merck only recently learned of this editorial. We have not had an opportunity to formally respond in the New England Journal of Medicine given the timing of its publication. Therefore, Merck looks forward to providing a more complete response to the editorial in the New England Journal of Medicine.

Vioxx is regularly prescribed for treatment of arthritis and acute pain in adults including the pain associated with menstrual cycles. It was recently approved for use in children suffering from rheumatoid arthritis.

The increased risks began surfacing 18 months into a three year study designed to analyze Vioxx’s effectiveness in preventing the recurrence of colorectal polyps. Such polyps sometimes become cancerous. Patients in the clinical study taking Vioxx were twice as likely to suffer from stroke or heart attack as those taking placebo. The study was halted as a result of the findings.

Vioxx was FDA approved in May 1999. A June 2000 study—VIGOR (VIOXX GI Outcomes Research)—first indicated the connection between Vioxx and heart attacks, raising health concerns about chronic use of the drug. As late as September of 2001, the FDA sent a warning letter to Merck accusing it of glossing over these findings in their advertising and other literature. The FDA’s letter mentions, among other things, a press release issued in May of 2001:

We have identified a Merck press release entitled, “Merck Confirms Favorable Cardiovascular Safety Profile of Vioxx,” dated May 22, 2001, that is also false or misleading for similar reasons stated above. Additionally, your claim in the press release that Vioxx has a “favorable cardiovascular safety profile,” is simply incomprehensible, given the rate of MI [myocardial infarctions] and serious cardiovascular events compared to naproxen. The implication that Vioxx’s cardiovascular profile is superior to other NSAIDS is misleading; in fact, serious cardiovascular events were twice as frequent in the VIOXX treatment group (101 events, 2.5%) as in the naproxen treatment group (46 events, 1.lYo) in the VIGOR study.

According to CNN.com, about 2 million people worldwide are on Vioxx (rofecoxib), which is the 16th most used drug in the U.S. Although, CNN.com also reported that “Vioxx sales have been flat in recent years amid safety concerns.” Doctors instead turned to Celebrex and Bextra, neither of which have been linked to heart attack and stroke. Nonetheless, Vioxx was a major revenue source for Merck, with worldwide sales totaling some $2.55 billion last year.

If you are currently taking Vioxx, the FDA and Merck urge you to contact your physician to investigate alternative treatments. Pharmacists will not fill any outstanding prescriptions for the drug.

Vioxx Press Releases

• FDA Issues Public Health Advisory on Vioxx as its Manufacturer Voluntarily Withdraws the Product
• Questions & Answers about Vioxx (FDA’s site)
• Merck Announces Voluntary Worldwide Withdrawal of VIOXX®

From CNN.com

• Doctor tells panel Vioxx raises heart attack risk. Thursday, February 17, 2005 Posted: 10:46 AM EST (1546 GMT)
• Report: Merck knew Vioxx unsafe in 2000. Monday, November 15, 2004 Posted: 10:16 AM EST (1516 GMT)
• Arthritis drug Vioxx being pulled. Thursday, September 30, 2004 Posted: 9:59 AM EDT (1359 GMT).

Merck is withdrawing Vioxx from the market after the data safety monitoring board overseeing a long-term study of the drug recommended that the study be halted because of an increased risk of serious cardiovascular events, including heart attacks and strokes, among study patients taking Vioxx compared to patients receiving placebo. The study was being done in patients at risk of developing recurrent colon polyps.

“Merck did the right thing by promptly reporting these findings to FDA and voluntarily withdrawing the product from the market,” said Acting FDA Commissioner Dr. Lester M. Crawford. “Although the risk that an individual patient would have a heart attack or stroke related to Vioxx is very small, the study that was halted suggests that, overall, patients taking the drug chronically face twice the risk of a heart attack compared to patients receiving a placebo.”

Dr. Crawford added that FDA will closely monitor other drugs in this class for similar side effects. “All of the NSAID drugs have risks when taken chronically, especially of gastrointestinal bleeding, but also liver and kidney toxicity. They should only be used continuously under the supervision of a physician.”

FDA approved Vioxx in 1999 for the reduction of pain and inflammation caused by osteoarthritis, as well as for acute pain in adults and for the treatment of menstrual pain. It was the second of a new kind of NSAID (Cox-2 selective) approved by FDA. Subsequently, FDA approved Vioxx to treat the signs and symptoms of rheumatoid arthritis in adults and children.

At the time that Vioxx and other Cox-2 selective NSAIDs were approved, it was hoped that they would have a lower risk of gastrointestinal ulcers and bleeding than other NSAIDs (such as ibuprofen and naproxen). Vioxx is the only NSAID demonstrated to have a lower rate of these side effects.

Merck contacted FDA on September 27, 2004, to request a meeting and to advise the agency that the long-term study of Vioxx in patients at increased risk of colon polyps had been halted. Merck and FDA officials met the next day, September 28, and during that meeting the company informed FDA of its decision to remove Vioxx from the market voluntarily.

In June 2000, Merck submitted to FDA a safety study called VIGOR (Vioxx Gastrointestinal Outcomes Research) that found an increased risk of serious cardiovascular events, including heart attacks and strokes, in patients taking Vioxx compared to patients taking naproxen. After reviewing the results of the VIGOR study and other available data from controlled clinical trials, FDA consulted with its Arthritis Advisory Committee in February 2001 regarding the clinical interpretation of this new safety information. In April 2002, FDA implemented labeling changes to reflect the findings from the VIGOR study. The labeling changes included information about the increase in risk of cardiovascular events, including heart attack and stroke.

Recently other studies in patients taking Vioxx have also suggested an increased risk of cardiovascular events. FDA was in the process of carefully reviewing these results, to determine whether further labeling changes were warranted, when Merck informed the agency of the results of the new trial and its decision to withdraw Vioxx from the market.

Additional information about this withdrawal of Vioxx, as well as questions and answers for patients, is available online at http://www.fda.gov/cder/drug/infopage/vioxx/default.htm.

The trial, which is being stopped, was designed to evaluate the efficacy of VIOXX 25 mg in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas. In this study, there was an increased relative risk for confirmed cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking VIOXX compared to those taking placebo. The results for the first 18 months of the APPROVe study did not show any increased risk of confirmed cardiovascular events on VIOXX, and in this respect, are similar to the results of two placebo-controlled studies described in the current U.S. labeling for VIOXX.

“We are taking this action because we believe it best serves the interests of patients,” said Raymond V. Gilmartin, chairman, president and chief executive officer of Merck. “Although we believe it would have been possible to continue to market VIOXX with labeling that would incorporate these new data, given the availability of alternative therapies, and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take.”

APPROVe was a multi-center, randomized, placebo-controlled, double-blind study to determine the effect of 156 weeks (three years) of treatment with VIOXX on the recurrence of neoplastic polyps of the large bowel in patients with a history of colorectal adenoma. The trial enrolled 2,600 patients and compared VIOXX 25 mg to placebo. The trial began enrollment in 2000.

VIOXX was launched in the United States in 1999 and has been marketed in more than 80 countries. In some countries, the product is marketed under the trademark CEOXX. Worldwide sales of VIOXX in 2003 were $2.5 billion.

Results of the VIGOR (VIOXX Gastrointestinal Outcomes Research) study, released in March 2000, demonstrated that the risk of gastrointestinal toxicity with VIOXX was less than with naproxen, but indicated an increased risk of cardiovascular events versus naproxen. However, in other studies including Merck’s Phase III studies that were the basis of regulatory approval of the product, there was not an increased risk of cardiovascular events with VIOXX compared with placebo or VIOXX compared with other non-naproxen non-steroidal anti-inflammatory drugs (NSAIDs). Merck began long-term randomized clinical trials to provide an even more comprehensive picture of the cardiovascular safety profile of VIOXX.

“Merck has always believed that prospective, randomized, controlled clinical trials are the best way to evaluate the safety of medicines. APPROVe is precisely this type of study – and it has provided us with new data on the cardiovascular profile of VIOXX,” said Peter S. Kim, Ph.D., president of Merck Research Laboratories. “While the cause of these results is uncertain at this time, they suggest an increased risk of confirmed cardiovascular events beginning after 18 months of continuous therapy. While we recognize that VIOXX benefited many patients, we believe this action is appropriate.”

Merck has informed the U.S. Food and Drug Administration and regulatory authorities in other countries of its decision. The company also is in the process of notifying health care practitioners in the United States and other countries where VIOXX is marketed. Patients who are currently taking VIOXX should contact their health care providers to discuss discontinuing use of VIOXX and possible alternative treatments. In addition, patients and health care professionals may obtain information from www.merck.com and www.vioxx.com, or may call (888) 36-VIOXX (1-888-368-4699).

The results of clinical studies with one molecule in a given class are not necessarily applicable to others in the class. Therefore, the clinical significance of the APPROVe trial, if any, for the long-term use of other drugs in this class, consisting of COX-2 specific inhibitors and NSAIDs, is unknown. The company will work with regulatory authorities in the 47 countries where ARCOXIA is approved to assess whether changes to the prescribing information for this class of drugs, including ARCOXIA, are warranted. Merck is continuing to seek approval for ARCOXIA in other countries, including the United States.

Merck will continue its extensive clinical program to collect additional longer-term data for ARCOXIA, its medication for arthritis and acute pain.

With regard to financial guidance, prior to today’s announcement, Merck remained comfortable with its 2004 earnings per share guidance of $3.11 to $3.17. The company currently expects earnings per share to be negatively affected by $0.50 to $0.60 as a result of today’s announcement. This estimate includes foregone sales, writeoffs of inventory held by Merck, customer returns of product previously sold and costs to undertake the pullback of the product. Included in this cost estimate is the expectation of foregone fourth quarter sales of VIOXX of $700 million to $750 million. In addition, Merck expects that worldwide approximately one month of inventory is held by customers and will be returned.

At this point it is uncertain which of these costs will be recorded in the third quarter and which will be recorded in the fourth quarter. Therefore, at this point, Merck is retracting the third quarter guidance it had previously provided.

Merck will report third-quarter earnings on Oct. 21. At that point, the company will provide additional information regarding the costs for product withdrawal.

The results of the Vioxx Gastrointestinal Research study were first released in March 2000. Since that time, the data have been widely reported, published in The New England Journal of Medicine and discussed extensively by an FDA Advisory Committee.

In VIGOR, Vioxx 50 mg, a dose two-times the highest chronic dose approved for osteoarthritis, significantly reduced the risk of serious GI side effects by half compared to a commonly used dose of naproxen (1,000 mg) in rheumatoid arthritis patients. The Advisory Committee recommended that these results be included in the labeling for Vioxx. Vioxx is not indicated for rheumatoid arthritis.

Although the VIGOR study was a GI outcomes study and was not designed to show differences in cardiovascular effects, significantly fewer heart attacks were observed in patients taking naproxen (0.1 percent) compared to the group taking Vioxx 50 mg (0.5 percent) in this study. There was no difference in cardiovascular mortality between the groups treated with Vioxx or naproxen. Patients taking aspirin did not participate in VIGOR.

In extensive discussions, the Advisory Committee explored this finding, other studies of Vioxx and possible explanations for this result in VIGOR. In the completed osteoarthritis trials and on-going clinical trials with Vioxx 12.5 mg, 25 mg and 50 mg in 30,000 patients, there was no difference in the incidence of cardiovascular events, such as heart attacks, among patients taking Vioxx, other NSAIDs and placebo.

At the Advisory Committee meeting, Merck scientists said the VIGOR finding is consistent with naproxen’s ability to block platelet aggregation by inhibiting COX-1 like aspirin, which is used to prevent second cardiac events in patients with a history of heart attack, stroke or other cardiac events. This is the first time this effect of naproxen on cardiovascular events has been observed in a clinical study. Other potential explanations were advanced by the FDA reviewer and were discussed with the Advisory Committee. The Committee recommended that the data on cardiovascular events in VIGOR be included in the labeling for Vioxx.

In addition, the Committee agreed that the prescribing information for both Vioxx and Celebrex(R) (celecoxib) should reflect the fact that neither of these selective NSAIDs confer cardioprotective benefits and are not a substitute for low-dose aspirin. The Committee also recommended that other studies be conducted to further explore the safety of concomitant use of selective NSAIDs and low-dose aspirin.

In a separate GI outcomes study in osteoarthritis and rheumatoid arthritis patients, celecoxib, another agent that selectively inhibits COX-2, was compared to the NSAIDs diclofenac and ibuprofen. Pharmacia, maker of celecoxib, has indicated that there were no differences among celecoxib, ibuprofen and diclofenac on these cardiovascular events. In Pharmacia’s background package submitted to the FDA for the Advisory Committee meeting, the incidence of patients taking celecoxib who experienced a heart attack was cited as 0.5 percent, 0.3 percent among diclofenac patients, and 0.5 percent among patients taking ibuprofen.

Important information about Vioxx

The recommended dose of Vioxx for the treatment of osteoarthritis is 12.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 25 mg once daily.

Serious stomach problems, such as bleeding, can occur without warning symptoms. Administration of low-dose aspirin with Vioxx may result in an increased rate of GI ulcers or other complications compared to use of Vioxx alone. Physicians and patients should remain alert for signs and symptoms of gastrointestinal bleeding.

Common side effects reported in osteoarthritis clinical trials with Vioxx were upper-respiratory infection, diarrhea, nausea and high blood pressure. People who have had an allergic reaction to Vioxx, aspirin or other NSAIDs should not take Vioxx. Safety and effectiveness in children below the age of 18 have not been studied.

Merck & Co., Inc. (NYSE: MRK) is a global, research-driven pharmaceutical company that discovers, develops, manufactures and markets a broad range of human and animal health products, directly and through its joint ventures, and provides pharmaceutical benefit services through Merck-Medco Managed Care.

Vioxx(R) is the Merck registered trademark for rofecoxib.