A second cholesterol drug poses hazards, may spawn suits.

A widely used cholesterol-lowering drug that is alleged to cause kidney failure or insufficiency may soon be the subject of lawsuits around the country, echoing litigation over the health hazards of Baycol, a similar drug withdrawn from the market five years ago. Manufactured by London-based AstraZeneca, Crestor (rosuvastatin calcium) is still on the market and has been used by more than 4.3 million patients in more than 70 countries.

Like Baycol (cerivastatin), Crestor is one of a class of drugs called statins, used in patients who have high cholesterol levels and are at risk for atherosclerosis--a hardening or thickening of the arteries. Statins block the production of enzymes the body uses to make cholesterol in the liver. By reducing the production of low-density lipoprotein (LDL)--the so-called bad cholesterol that causes plaque to build up in arteries--statins decrease the patient's risk of a stroke or heart attack. Five other statins are currently on the U.S. market: Lipitor (atorvastatin), Lescol (fluvastatin), Mevacor (lovastatin), Pravachol (pravastatin), and Zocor (simvastatin).

But some consumer advocates say Crestor is dangerous, and the Web site WorstPills.org, maintained by the Washington, D.C.-based Public Citizen Health Research Group (HRG), has designated Crestor a "Do Not Use" drug.

"This drug has unique dangers compared with all the other statins currently on the market," said Sidney Wolfe, a physician who heads HRG. "There is an increased risk of rhabdomyolysis, which is an often-fatal destruction of the muscle, and an increased risk of renal disease. Rhabdomyolysis can cause renal disease, but [Crestor can cause] renal disease in people who did not have rhabdomyolysis. Those are the two unique risks, and the drug offers no unique benefits."

Mark Robinson Jr., a Newport Beach, California, lawyer who represents plaintiffs in pharmaceutical cases, said AstraZeneca has misrepresented or omitted facts about adverse health effects in its advertising and marketing materials.

"It seems like every time you turn on the TV you see an ad for Crestor. Patients are given a nice picture of the drug, but the side-effect profile is not clear," he said.

A troubled history

Crestor's problems began before the FDA approved it in August 2003. When AstraZeneca submitted its New Drug Application to the agency in June 2001, two safety issues came up in the first review cycle: six cases of rhabdomyolysis among 1,365 patients exposed to the 80-mg dose, and urine abnormalities--specifically, protein and blood in the urine in some patients.

The rhabdomyolysis finding was notable because in 2001, Bayer Pharmaceuticals voluntarily (with the FDA's support) withdrew Baycol from the market after the FDA received 31 reports of fatal rhabdomyolysis linked to the drug. (See Rebecca Porter, Attorneys Press Discovery Effort in Litigation over Cholesterol Drug, TRIAL, June 2003, at 12.)

The FDA approved Crestor in doses of 5, 10, 20, and 40 mg, but not the 80-mg dose. It also required AstraZeneca to provide more extensive data to address concerns about muscle and renal toxicity.

HRG opposed the drug's approval, and after losing that battle, it petitioned the FDA to require that the drug be withdrawn from the market. The agency declined last March.

"Our review of all the available evidence (including preclinical data, premarketing clinical studies, Phase 4 clinical studies, and post-marketing adverse event reports) indicates that Crestor does not pose a risk of muscle toxicity greater than that of other approved statins. With respect to renal toxicity, there is no convincing evidence that Crestor poses a risk of serious renal injury," the FDA said. "However, to help ensure the safe and effective use of Crestor, AstraZeneca has revised the labeling to address certain concerns regarding dose-related risks, proper doses, and other matters related to information from adverse event reports and Phase 4 studies."

AstraZeneca reiterated its claim that its product is safe. "Patient safety is our top priority, and the FDA's rejection of Public Citizen's petition should reassure the millions of people who have been unnecessarily alarmed by HRG's allegations," AstraZeneca U.S. President and CEO David Brennan said in a statement.

Wolfe called the changes in Crestor's labeling "cosmetic" and said they will have no significant impact. When doctors start prescribing a drug, they consult the labeling, he said, but after that, they rarely notice even major labeling changes.

At least one study supports HRG's concerns about the drug. In an article published last May in Circulation, the journal of the American Heart Association, researchers from Tufts-New England Medical Center's Molecular Cardiology Research Center reported their finding that Crestor isn't as safe as three other statins--Lipitor, Pravachol, and Zocor.

Lead author Richard Karas and three colleagues analyzed 145 rosuvastatin-associated adverse events during Crestor's first year of marketing and found that the drug was significantly more likely to be associated with rhabdomyolysis, proteinuria (protein in the urine), or kidney failure than the other statins. (Alawi A. Alsheikh-Ali et al., The Safety of Rosuvastatin as Used in Common Clinical Practice: A Postmarketing Analysis, 111 Circulation 3051-57 (2005).)

"This study raises concern about the safety of this drug at the range of doses currently used in common clinical practice in the general population," Karas said in a press release issued by Tufts. "I would advise health care providers to consider other statins as first-line therapy, to initiate therapy in appropriate patients at lower doses, to consider combination [cholesterol]lowering therapy, and to closely monitor patients for adverse events if rosuvastatin (Crestor) is used."

AstraZeneca spokeswoman Emily Denney cited shortcomings in the study. "Only the number of spontaneous event reports for Crestor through 2004 were considered, whereas important issues concerning causality or confounding factors were not," Denney said.

Robinson, whose firm represents more than a dozen clients alleging they were injured by Crestor, said the cases involve classic failure-to-warn claims. The plaintiffs allege that the manufacturer failed to warn patients about the increased risk of kidney problems (as compared with other statins) when the drug went on the market and overpromoted it without disclosing those risks.

Steven Skikos, a San Francisco lawyer, said his firm is currently evaluating cases. "The direct-to-consumer ads are leading us to believe that we have potential failure-to-warn and negligence claims, and possibly fraud," he said. "In most cases, pharmaceutical companies market their products appropriately, but in this case they did not."

In some states, a manufacturer may be held liable if aggressive marketing leads health care providers to overlook a drug's dangers despite warnings. (See Gerald D. Jowers Jr., Drug Advertising &Accountability, TRIAL, July 2003, at 68.) Robinson cited the California Supreme Court's decision in Stevens v. Park, Davis & Co., holding that a manufacturer's overpromotion of a drug undermines its warning labels. (107 Cal. Rptr. 45, 54 (1973).)

"In California, evidence of a subsequent change in your warning is admissible in evidence to prove there was an initial failure to warn," Robinson said.

Wolfe said his organization plans to continue warning patients against using Crestor. "More and more of these cases are occurring. People are being severely injured and in some cases killed by this drug," he said.