Merck's Reply - Vioxx

In response to news and analyst reports of data the Company first released a year ago, Merck & Co., Inc. today reconfirmed the favorable cardiovascular safety profile of Vioxx(R) (rofecoxib), its medicine that selectively inhibits COX-2. Vioxx was approved by the Food and Drug Administration in May 1999 for the management of osteoarthritis and the relief of acute pain in adults based on efficacy and safety studies involving nearly 4,000 patients. More than 33 million prescriptions have been written for Vioxx in the United States since its introduction.

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.

Pharmacia and Pfizer's Reply - Celebrex In response to today's New York Times article, Pharmacia Corporation and Pfizer Inc issued the following statement:

The COX-2 specific inhibitors represent a major medical advance in the treatment of arthritis. Pharmacia and Pfizer maintain that molecular differences between the COX-2 specific inhibitors may account for the cardiovascular and renal safety differences seen between Celebrex(R) (celecoxib capsules) and Vioxx(R).

Pharmacia and Pfizer note that all clinical trials of Celebrex to date, representing over 30,000 patients and nearly two million patient-years of exposure, have shown no increased risk for heart attack and stroke, compared to traditional NSAIDs studied. These data include the studies done to support the initial celecoxib new drug application, the Celecoxib Long-term Arthritis Safety Study (CLASS), and other post approval clinical trials.

In fact, data from two recent head-to-head studies of Celebrex 200 mg once-a-day and Vioxx 25 mg once-a-day demonstrated that osteoarthritis patients over 65 years of age with high blood pressure taking Vioxx experienced statistically significant and clinically meaningful increases in systolic blood pressure (SBP) and edema, compared to patients taking Celebrex. These studies were presented at this year's annual meetings of the American College of Cardiology and the American Geriatric Society.

"These studies substantially add to our understanding of differences between the overall cardiovascular safety profile of COX-2 specific inhibitors, as experienced by clinically relevant populations," said William B. White, MD, professor of medicine and chief, section of hypertension and clinical pharmacology at the University of Connecticut School of Medicine in Farmington. "They also provide compelling evidence that all COX-2 specific inhibitors are not the same," Dr. White added.

The two companies acknowledge that Celebrex is not a cardioprotective agent and should not be substituted as such for aspirin, in a population at risk for cardiovascular disease.

Additional Information

Celebrex is the only COX-2 specific inhibitor approved for osteoarthritis (OA) and adult rheumatoid arthritis (RA).

Celebrex should not be taken by patients who have aspirin-sensitive asthma or allergic reactions to aspirin or other arthritis medicines or certain sulfa drugs called sulfonamides, or who are in their third trimester of pregnancy. As with all NSAIDs, serious GI tract ulcerations can occur without warning symptoms. Physicians and patients should remain alert to the signs and symptoms of GI bleeding. Celebrex does not affect platelet function and therefore should not be used for cardiovascular prophylaxis. As with all NSAIDs, Celebrex(R) should be used with caution in patients with fluid retention, hypertension, or heart failure. In clinical studies the most common side effects of Celebrex were dyspepsia, diarrhea and abdominal pain, which were generally mild to moderate.

There have been infrequent post-marketing reports of increases in prothrombin time, sometimes associated with bleeding events, predominantly in the elderly. Anticoagulant activity should be monitored when therapy with Celebrex is initiated or changed in patients taking warfarin, particularly in the first few days.