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9/30/2004

Merck Withdraws Rofecoxib From Worldwide Market

Cheryl A. Thompson

New research showing an increased risk of myocardial infarction and stroke in patients using rofecoxib, or Vioxx, for longer than 18 months has prompted Merck & Co. Inc. to withdraw the product from the market, the company announced today.

The withdrawal of the cyclooxygenase type 2 (COX-2) inhibitor is immediate, and the firm advised rofecoxib users to contact their health care provider to discuss stopping the therapy and managing their arthritis or acute pain with another medication.

Return All Rofecoxib Supplies

Pharmacists should stop dispensing rofecoxib and expect to receive instructions on returning their supply of the drug, according to a letter (PDF) from Merck.

The company has contracted National Notification Center (NNC) in Indianapolis to handle the return of rofecoxib from pharmacies and patients.

Merck said NNC will contact pharmacies in the next five business days to provide instructions on returning for "appropriate credit" all rofecoxib tablets and oral suspension that have not been dispensed.

According to the letter to pharmacists, patients who want to return their supply of rofecoxib and be reimbursed for the cost of their unused tablets or oral suspension must provide:

  • Their name, address, and phone number,
  • The unused product in the container dispensed by the pharmacy, and
  • The pharmacy receipt for the product being returned.

Although Merck originally told patients seeking a refund to send their unused rofecoxib via the U.S. mail, the company recently changed its instruction. Patients seeking a refund should contact NNC at 800-805-9542 to obtain a mailing kit with prepaid postage.

Arthur A. Schuna, a pharmacist specializing in rheumatology at the William S. Middleton Veterans Affairs Medical Center in Madison, Wis., said pharmacists have several options to consider in recommending a new therapy for patients who have been using rofecoxib.

But first, he said, pharmacists should determine why the patients have been receiving rofecoxib. "Did they have a [gastrointestinal] bleed or not? How at risk are they?"

Patients at high risk of gastrointestinal (GI) bleeding, he said, can use either of the other available COX-2 inhibitors: celecoxib or valdecoxib.

Neither celecoxib nor valdecoxib has been linked to an increased risk of myocardial infarction or stroke in users, according to the products' official labeling. COX-2 inhibitors have had a general reputation for being gentler on patients' upper GI tract than conventional nonsteroidal antiinflammatory drugs, which can cause bleeding.

A third option, he said, is meloxicam at a low dosage.

"However, none of these three options," he cautioned, "have been shown in clinical trials to reduce the risk of serious GI bleed."

A fourth option is a conventional nonsteroidal antiinflammatory drug accompanied by a proton-pump inhibitor, such as omeprazole. Addition of a proton-pump inhibitor, he said, has been shown to reduce the risk of GI bleeding in users of nonsteroidal antiinflammatory drugs.

Schuna said a conventional analgesic, such as acetaminophen, is an option for patients with less-severe pain. Patients with a chronic pain disorder, he said, may be candidates for propoxyphene or tramadol at a low dosage.

Abrupt replacement of rofecoxib with another medication should not pose a problem, he said, except in patients also receiving warfarin therapy. Rofecoxib is known to increase the International Normalized Ratio, a measure of anticoagulation, in warfarin users. Withdrawal of rofecoxib from a warfarin user's medication regimen may require adjustment of the anticoagulant's dosage, he said.

The increased risk of cardiovascular events, according to Merck, was discovered in an analysis of data from patients who had completed three years in the Adenomatous Polyp Prevention on VIOXX study, which sought to determine whether long-term rofecoxib therapy can prevent the recurrence of colorectal adenoma. Participating patients were randomly assigned to receive rofecoxib 25 mg/day or a placebo for three years. A check on the data from 18 months of rofecoxib therapy did not show an increased risk of "confirmed cardiovascular events," such as myocardial infarction and stroke, the company said, but the data from 36 months of use did.

Merck on Monday notified the Food and Drug Administration (FDA) of the increased risk to long-term rofecoxib users and, on Tuesday, told officials of the decision to remove the drug from the market, said Steven Galson, acting director of the agency's Center for Drug Evaluation and Research (CDER). He told reporters that Merck personnel made the decision without any prompt from FDA.

John Jenkins, another CDER official, said the study involved 2600 adults, about 1300 in each group. From a safety standpoint, he said, the study looked foremost at confirmed thromboembolic events.

A confirmed thromboembolic event occurred in 3.5 percent of the rofecoxib users but only 1.9 percent of the patients assigned to the placebo group, Jenkins said. Five patients in each group died of the thromboembolic event, he said.