Baycol, one of a family of popular cholesterol-lowering drugs, was pulled from the U.S. market by its manufacturer Wednesday because of reports linking the pill to 31 deaths.

According to the manufacturer, Bayer Corp., all of the deaths involved rhabdomyolysis, a painful disorder that destroys muscle tissue. The "vast majority" of those who died had developed kidney failure, a company executive said.

Baycol, approved by the Food and Drug Administration in mid-1997, is the 12th prescription drug to be withdrawn for safety reasons within the last four years. Nine of the drugs were approved since 1993, when the FDA has been under strong bipartisan pressure in Washington to accept more products developed by the $100-billion pharmaceutical industry.

Since Baycol's introduction to the American market in February 1998, it has generated sales topping $615 million and presently accounts for about 7% of prescriptions filled and refilled for cholesterol-lowering drugs. About 10.6 million new and refilled prescriptions have been dispensed for Baycol, according to IMS Health, an industry information service.

More than 700,000 people in this country take Baycol, which is in a class of cholesterol-lowering drugs known as statins. Five other statins remain on the U.S. market as alternatives: Mevacor, Pravachol, Zocor, Lescol and Lipitor.

Rhabdomyolysis is a risk with all statins, the most-prescribed class of drugs in America. About 12 million people are taking the pills.

But in a prepared statement Wednesday, the FDA said that drug-related deaths from rhabdomyolysis in the U.S. "have been reported significantly more frequently [with Baycol] than for other approved statins." The agency said it "agrees with and supports" Bayer's decision to withdraw Baycol.

Symptoms of rhabdomyolysis include muscle pain, tenderness and weakness--most commonly in the calves and lower back.

"Any patient who has muscle pain and is taking a statin should contact their physician," said an FDA spokeswoman, Laura Bradbard. Malaise, fever, dark urine or nausea can also be symptoms. Doctors said that kidney failure and death can usually be averted if a patient with rhabdomyolysis promptly stops taking the drug.

Dr. Beatrice Alexandra Golomb, a UC San Diego specialist who is conducting a five-year study of two other statin drugs under a grant from the National Institutes of Health, said awareness of rhabdomyolysis is low among both physicians and patients.

"The issue of rhabdomyolysis obviously requires concern because people die from it," Golomb said. "Awareness needs to be enhanced. . . . They're wonderful drugs--in the right people."

FDA records show that when he recommended approval of Baycol on May 29, 1997, an agency medical officer, Dr. David G. Orloff, cited rhabdomyolysis as one of four "potentially serious adverse effects" that concerned him. However, no instances of rhabdomyolysis were reported in Bayer's original clinical studies of the drug among 3,343 patients in the U.S., Japan and China.

According to Dr. Paul MacCarthy, Bayer's vice president of U.S. medical science, the company voluntarily approached the FDA in December 1999 with a proposal to warn against prescribing Baycol in combination with Lopid, a drug that lowers a fatty substance in the blood, because of reports of rhabdomyolysis. Bayer informed doctors and other health care providers of the safety-labeling change in a mass-mailed letter.

In an interview from company offices in West Haven, Conn., MacCarthy said that Bayer again approached the FDA in April of this year after fatal cases of rhabdomyolysis persisted. The labeling was changed, effective in June, to warn doctors not to place patients on the maximum dose of 0.8 milligram without first trying lower doses. An accompanying letter to health care providers warned anew against prescribing the drug with Lopid.

The withdrawal announced Wednesday came just two months after the last safety-labeling change. MacCarthy said the company found that, despite the explicit warnings, doctors had continued to prescribe Baycol with Lopid and to start patients at the maximum dose.

"Since this involved fatalities, we determined that this [the withdrawal] is the appropriate thing to do in the interest of patient safety," MacCarthy said, adding that Bayer was "likely to close" ongoing clinical studies of Baycol, including experiments assessing the drug's effect on bone density and stroke prevention. The company is withdrawing the drug worldwide except for Japan, where neither the 0.8-milligram dose nor the other drug, Lopid, is used.

But the danger is not limited to the combined use of Baycol and Lopid. Nineteen of the 31 U.S. deaths cited by the FDA involved the use of Baycol without Lopid. And because side effects from prescription drugs are reported voluntarily in the U.S., epidemiologists believe the incidence of harm is consistently underreported.

The withdrawal of Baycol amounts to another repudiation of the FDA's frequent use of safety-labeling changes as tools to reduce risk, according to some experts.

"It re-raises the question about people hiding behind labeling changes," said Dr. Alastair J.J. Wood, a former FDA advisory committee member who is a professor of medicine and pharmacology at Vanderbilt University.

Said Dr. Raymond L. Woosley, the former pharmacology department chairman at Georgetown University, "It shouldn't have taken nearly four years. This [rhabdomyolysis] was a known reaction and consequence. . . . This drug was used in hundreds of thousands of people."

Dr. Sidney Wolfe of the consumer group Public Citizen said the organization is preparing a petition that will urge the FDA to impose new safety warnings on the five statin drugs that remain on the market.

"All the statins cause rhabdomyolysis," he said. "Even with Baycol off the market, people should be made aware of it."

Wolfe also said he would write to authorities in Japan, urging them too to take Baycol off the market.

In addition to Baycol, the other 11 drugs withdrawn since September 1997 were: Raplon, Lotronex, Propulsid, Rezulin, Raxar, Posicor, Duract, Hismanal, Seldane, Redux and Pondomin.

The withdrawal of yet another recently approved drug should prompt Congress to more closely scrutinize the performance of the FDA, said Daniel W. Sigelman, who in the 1980s served as counsel to the House Subcommittee on Human Resources and Intergovernmental Relations.

"This underscores the urgent need for Congress to resume investigations of FDA's efforts to protect the public from unsafe drugs," said Sigelman, whose law firm has sued at least one major drug manufacturer. "Regrettably, for many years now, Congress has abdicated its responsibility here."

From the Los Angeles Times
August 9, 2000