Vioxx Withdrawn After Study Suggests It May Double the Risk of Heart Attack

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Vioxx Withdrawn After Study Suggests It May Double the Risk of Heart Attack

Increased risk of serious cardiovascular events, including heart attacks and strokes, found in test of arthritis drug

Sept. 30, 2004 – In a stunning announcement today, drug-maker Merck & Co. announced the withdrawal of the popular anti-inflammatory drug Vioxx from the market due to a study they were conducting that shows patients taking the drug face twice the risk of heart attack compared to those in the test taking a placebo. The FDA, that approved the drug in 1999, also issued a public health advisory and news release. It is used by many senior citizens for arthritis.

“Vioxx is a prescription COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) that was approved by FDA in May 1999 for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of menstrual symptoms. It is also approved for the relief of the signs and symptoms of rheumatoid arthritis in adults and children,” says the FDA.

The health advisory said, “The risk that an individual patient taking Vioxx will suffer a heart attack or stroke related to the drug is very small. Patients who are currently taking Vioxx should contact their physician for guidance regarding discontinuation and alternative therapies.’

FDA is working closely with Merck to coordinate the withdrawal of this product from the U.S. market place. Healthcare professionals are advised to contact Merck at 1-888-368-4699 or at www.merck.com or at the FDA’s Drug Information Office at 301-827-4573 or 1-888-463-6332 or go to Vioxx Information on FDA’s website for questions about this product.

The Food and Drug Administration (FDA) today acknowledged the voluntary withdrawal from the market of Vioxx (chemical name rofecoxib), a non-steroidal anti-inflammatory drug (NSAID) manufactured by Merck & Co. FDA today also issued a Public Health Advisory to inform patients of this action and to advise them to consult with a physician about alternative medications.

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.

WHITEHOUSE STATION, N.J., Sept. 30, 2004 - Merck &. Co., Inc. today announced a voluntary worldwide withdrawal of VIOXX® (rofecoxib), its arthritis and acute pain medication. The company's decision, which is effective immediately, is based on new, three-year data from a prospective, randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial.

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.

About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health, directly and through its joint ventures.

Forward Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2003, and in its periodic reports on Form 10-Q and Form 8-K (if any), which the company incorporates by reference.

Merck & Co., Inc. today announced a voluntary withdrawal of Vioxx from the U.S. market due to safety concerns. Vioxx is a prescription COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) that was approved by FDA in May 1999 for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of menstrual symptoms. It is also approved for the relief of the signs and symptoms of rheumatoid arthritis in adults and children.

The Agency was informed by Merck & Co., Inc. on September 27, 2004, that the Data Safety Monitoring Board for an ongoing long-term study of Vioxx (APPROVe) had recommended that the study be stopped early for safety reasons. The study was being conducted in patients at risk for developing recurrent colon polyps. The study showed an increased risk of cardiovascular events (including heart attack and stroke) in patients on Vioxx compared to placebo, particularly those who had been taking the drug for longer than 18 months. Based on this new safety information, Merck and FDA officials met the next day, September 28, 2004, and during that meeting FDA was informed that Merck was voluntarily withdrawing Vioxx from the market place.

The risk that an individual patient taking Vioxx will suffer a heart attack or stroke related to the drug is very small. Patients who are currently taking Vioxx should contact their physician for guidance regarding discontinuation and alternative therapies.

Merck & Co., Inc. announced a voluntary withdrawal of Vioxx (rofecoxib) from the U.S. and worldwide market due to safety concerns of an increased risk of cardiovascular events (including heart attack and stroke) in patients on Vioxx. Vioxx is a prescription COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) that was approved by FDA in May 1999 for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of menstrual symptoms, and was later approved for the relief of the signs and symptoms of rheumatoid arthritis in adults and children.

Vioxx is a COX-2 selective nonsteroidal anti-inflammatory drug (NSAID). Vioxx is also related to the nonselective NSAIDs , such as ibuprofen and naproxen. Vioxx is a prescription medicine used to relieve signs and symptoms of arthritis, acute pain in adults, and painful menstrual cycles.

No, Merck made this decision independent of input from FDA. The Agency has not had an opportunity to review the data from the study that was stopped in the depth that Merck has, but agrees with the company that there appear to be significant safety concerns for patients, particularly those taking the drug chronically.

FDA plans to work closely with Merck to coordinate the withdrawal of this product from the US market.

FDA issued a public health advisory concerning the use of Vioxx. This advisory is based on Merck & Co., Inc. voluntarily withdrawing Vioxx from the market due to safety concerns.

The risk that an individual patient will suffer a heart attack or stroke related to Vioxx is very small. We encourage people taking Vioxx to contact their physician to discuss discontinuing use of Vioxx and alternative treatments. Any decision about which drug product to take to treat your symptoms should be made in consultation with your physician based on an assessment of your specific treatment needs.

6. What are the likely long-term health effects, if any, of taking this product?

The new study shows that Vioxx may cause an increased risk in cardiovascular events such as heart attack and strokes during chronic use.

Merck’s decision to withdraw Vioxx from the market is based on new data from a trial called the APPROVe [ Adenomatous Polyp Prevention on VIOXX] trial. In the APPROVe trial, Vioxx was compared to placebo (sugar-pill). The purpose of the trial was to see if Vioxx 25 mg was effective in preventing the recurrence of colon polyps. This trial was stopped early because there was an increased risk for serious cardiovascular events, such as heart attacks and strokes, first observed after 18 months of continuous treatment with Vioxx compared with placebo.

The APPROVe trial began enrollment in 2000. The trial was being monitored by an independent data safety monitoring board (DSMB). It was not stopped earlier because the results for the first 18 months of the trial did not show any increased risk of confirmed cardiovascular events on Vioxx.

9. What did FDA know about the risk of heart attack and stroke when it approved Vioxx?

FDA originally approved Vioxx in May 1999. The original safety database included approximately 5000 patients on Vioxx and did not show an increased risk of heart attack or stroke. A later study, VIGOR (VIOXX GI Outcomes Research), was primarily designed to look at the effects of Vioxx on side effects such as stomach ulcers and bleeding and was submitted to the FDA in June 2000. The study showed that patients taking Vioxx had fewer stomach ulcers and bleeding than patients taking naproxen, another NSAID, however, the study also showed a greater number of heart attacks in patients taking Vioxx. The VIGOR study was discussed at a February 2001 Arthritis Advisory Committee and the new safety information from this study was added to the labeling for Vioxx in April 2002. Merck then began to conduct longer-term trials to obtain more data on the risk for heart attack and stroke with chronic use of Vioxx.

10. Is FDA’s expedited review process putting riskier drugs on the market?

No. Vioxx received a six-month priority review because the drug potentially provided a significant therapeutic advantage over existing approved drugs due to fewer gastrointestinal side effects, including bleeding. A product undergoing a priority review is held to the same rigorous standards for safety, efficacy, and quality that FDA expects from all drugs submitted for approval.

COX-2 selective NSAIDs on the market at this time are Celebrex (celecoxib) and Bextra (valdecoxib). Vioxx is also related to the nonselective NSAIDs, such as ibuprofen and naproxen. You should consult your physician to determine which treatment is right for you.

12. Does today’s action suggest that other drugs in the same class are dangerous?

The results of clinical studies with one drug in a given class do not necessarily apply to other drugs in the same class. All of the NSAIDs have risks when taken chronically, especially of gastrointestinal (stomach) bleeding, but also liver and kidney toxicity. Patients using these drugs for a long period of time (longer than two weeks) should be under the care of a physician.

FDA did not request a recall of Vioxx. This product is being voluntarily withdrawn from the market by Merck.

No, Merck is initiating a market withdrawal in the United States to the pharmacy level. This means Vioxx will no longer be available at pharmacies.

FDA encourages anyone aware of a serious adverse reaction to make a MedWatch report. You can report an adverse event in two ways: