Drug's Problems Raise Questions on Warnings

By PHILIP J. HILTS

hen Baycol, a cholesterol-lowering drug, was approved in 1997, it appeared to be a potentially lifesaving drug with few side effects. It had been tested on more than 3,000 patients, and no serious problems had turned up.

Baycol was a statin, one of a class of powerful anti- cholesterol drugs that save thousands of lives by preventing heart attacks and strokes. Six statins are now on the market in the United States, and about 12 million people take them. Statins have proved so effective that in May, a national panel said 36 million Americans should be taking them. Sales of Baycol alone were expected to reach $800 million this year.

But on Aug. 8, Baycol, also known by the generic name cerivastatin, was taken off the market. Its manufacturer, the German company Bayer A.G., took that step after 31 patients on the drug had died and the cases cast suspicion on Baycol.

The deaths were caused by a disorder called rhabdomyolysis, in which muscle cells break down, flooding the kidneys with masses of cellular waste. Death occurs if the kidneys are overwhelmed and shut down.

Experts say the story of Baycol shows the kind of communication failure that has occurred before and may well occur again with other drugs. When muscle problems and deaths linked to Baycol were reported, Bayer and the Food and Drug Administration warned doctors to be cautious in prescribing it, but the warnings failed to stem the problem, and Baycol finally had to be taken off the market. A more effective warning system is needed to alert doctors to drug side effects and problems, many in the medical profession say.

"If there is a dangerous cliff and people keeping falling off it," said Dr. Alistair J. J. Wood, a professor of pharmacology at Vanderbilt University, "you have to stop relying on the sign that says, `Dangerous Cliff Ahead.' Something additional is needed." Dr. Wood is a practitioner in the new field of pharmaco-epidemiology, the study of the use of drugs in society.

Problems with Baycol had become apparent by December 1999, more than two years after it went on the market, because several reports of deaths from rhabdomyolysis had come in. The F.D.A. and the drug's maker, Bayer, cooperated in warning patients and doctors how to avoid the trouble.

Doctors were advised not to start patients on the highest dose available and not to give patients both cerivastatin and Lopid, or gemfibrozil, a nonstatin drug that lowers blood triglyceride levels and cholesterol. Patients taking both seemed more likely to develop muscle problems, doctors were told. A little over a year later, a second warning was sent to doctors.

But reports of deaths linked to Baycol continued to come in, so it was taken off the market. The availability of other cholesterol-reducing drugs was a factor.

The problems with Baycol caught many patients by surprise. One patient who suspects her muscle problems were caused by Baycol, Charlotte Collins of Havelock, N.C., said: "I was standing up and just raising my foot to put on my pants, and my back gave out on me. The muscles stopped working."

Ms. Collins heard news reports about symptoms similar to hers, then responded to an advertisement placed by David Duffus, a lawyer in Greenville, N.C., to find Baycol patients having problems. She said she had not yet decided whether to sue.

Ripples from the Baycol case are still being felt.

The other anticholesterol drugs can also lead to the muscle disorder, but Baycol has been linked to the potentially fatal disorder at a rate that may be 10 times as high as the other drugs, for reasons yet unknown.

In the United States, Public Citizen's Health Research Group, a medical watchdog organization in Washington, petitioned the F.D.A. yesterday to put clearly visible warnings on the remaining anticholesterol drugs to try to prevent more injuries or deaths. The group wants the warnings presented to both doctors and patients. The European Medicines Evaluation Agency has said it will review its warnings for those drugs.

In a new report, the Health Research Group said it had found 81 reports of deaths from rhabdomyolysis linked to statin drugs other than cerivastatin since the late 1980's. Those drugs are used by more than 12 million patients. Baycol, in comparison, was associated with 31 deaths in less than four years in a patient population of 700,000 — a much higher rate of reported problems.

"These estimates are very conservative — we didn't count many possible cases," said Dr. Sidney Wolfe, director of the Health Research Group. "The other statin drugs apparently don't cause problems at the same rate cerivastatin did, but the problems for them are still very serious, more serious than people have suspected."

Because doctors and hospitals are not required to report adverse reactions, academic, industry and government statisticians have calculated that there were probably about 10 cases of side effects for each case reported to the F.D.A.

Any drugs that are beneficial, like the statins, can also cause unwanted side effects. But there are few tools available to make sure that doctors know about and heed warnings and safety instructions on drug labels.

Such warnings often fail to work, said Dr. Wood of Vanderbilt.

Last week in The Journal of the American Medical Association, F.D.A. doctors published a study based on such a case, that of a diabetes drug called Rezulin, or troglitzone. As a few reports associating Rezulin with liver failure came in, the federal drug agency and the drug's maker sent four separate warning letters to doctors, asking them to watch out for the problem and to order liver tests for patients taking the drug.

The F.D.A. study showed that most doctors did not get or did not heed the message. Even after four entreaties from the company and the drug agency, only 44.6 percent of the patients taking the drug got the recommended liver tests. Even though liver monitoring was supposed to continue monthly for such patients, only 5 percent of doctors were regularly testing the liver function of patients on the drug five months after the warnings.

Rezulin was pulled from the market in March 2000 after reports of more than 60 deaths caused by liver failure among patients taking the drug. Rezulin proved effective for many diabetics who could not otherwise keep their blood sugar levels under tight control, and the drug agency waited until two similar, but presumably safer, drugs became available before taking that step.