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Dangers of Rosuvastatin (Crestor) Identified Before and After FDA Approval

This letter, by Sidney Wolfe, M.D., appeared in the June 26, 2004 edition of The Lancet.

Sir – The lipid-lowering drug rosuvastatin is currently in the midst of the most heavily financed launch of a prescription drug ever. Here I present premarketing and postmarketing evidence of the dangers of the drug, and call for its removal from the market.

Detailed briefing documents including unpublished reviews of safety and efficacy data from clinical trials are now made public on the internet before all Food and Drug Administration (FDA) advisory committee meetings discussing the approval of a new drug. Documents for the July 9, 2003, meeting on rosuvastatin,[1] and the transcript of that meeting,[2] were the source of the preapproval data I present. FDA adverse event reporting system (AERS) reports up to April 13, 2004, obtained through the Federal Freedom of Information Act were the source of postmarketing data.

The preapproval documents state that “The data … show, for the first time, the development of severe myopathy and rhabdomyolysis in clinical trials submitted for the original approval of a new statin. This risk is clearly increased at the highest dose studied (80 mg), which has subsequently been discontinued from development. While the risks of myopathy at lower doses appear comparable to other marketed statins, these risks may increase in special populations in which patients are exposed to higher levels of drug (drug-drug interactions, renal impairment, Japanese descent).” There were eight cases of rhabdomyolysis, seven at 80 mg and one at 10 mg, in clinical trials.[1]

The preapproval documents also state that “80 mg of rosuvastatin has a high frequency of [creatine kinase] elevations (CK>10xULN=1.9%), between what was seen in clinical trials for cerivastatin doses of 0.4 mg (1.55%) and 0.8 mg (2.1%) and higher than seen for all other currently approved statins” and that “there is a higher incidence of myopathy (1.0%) and rhabdomyolysis (0.4%) observed in the clinical trials with 80 mg of rosuvastatin than reported in the original NDA or current labels for any of the currently approved statins.”[1]

The FDA stated at the meeting that “since safe and effective statins with a low risk for the development of rhabdomyolysis are already currently available, any future statins which would be approved need to have a comparable or lower risk for this adverse event.”[2] However, rosuvastatin was approved under the belief that doses lower than 80 mg would be much safer.

“… Rosuvastatin was also associated with renal findings not previously reported with other statins. A small percentage of patients exposed primarily to the 80 mg dose of rosuvastatin had an increased frequency of persistent proteinuria and hematuria, which in some patients was also associated with an increase in serum creatinine.” The figure (below), based on the documents,[1] shows a dose-related increase in haematuria and proteinuria, beginning with 1.3% of patients at 40 mg. None of the other statins showed any dose-related increase. “Out of all the patients enrolled in these trials only 3% had an increase in serum creatinine of >30% above baseline… However, in the subgroup of patients with dipstick-positive urine (>++ protein and >+ blood), the percentage of patients with an increase of serum creatinine of 30% over baseline was 14%, 16%, 24%, 33%, and 41% for 5 mg, 10 mg, 20 mg, 40 mg and 80 mg of rosuvastatin, respectively… These data suggest that some patients with greater levels of proteinuria and hematuria may progress to clinically relevant renal disease.”[1]

Three cases of renal insufficiency or renal failure during the trials in people using 80 mg were “of concern because they present with a clinical pattern, which is similar to the renal disease seen with rosuvastatin in these clinical trials. There is mild proteinuria associated with hematuria and the suggestion of tubular inflammation or necrosis… However, if they [proteinuria and hematuria] are the signals for the potential progression to renal failure in a small number of patients, this may represent an unacceptable risk since currently approved statins do not have similar renal effects.”[1]

A statistical review of the efficacy of rosuvastatin compared with higher doses of another statin found that there was no significant difference in the percentage LDL change from baseline between 5, 10, or 20 mg of rosuvastatin and four times as much atorvastatin (20, 40, or 80 mg, respectively).[3]

Since marketing began, there have been 18 additional cases of rhabdomyolysis, including 11 in the USA, even though the drug had only been on the market in that country for 7 months as of the April 13 date of the AERS data from the FDA. All of the latest ten U.S. cases had been reported in the 6 weeks before April 13. Two of the 18 patients were using 40 mg, five were using 20 mg, and 11 were using 10 mg. An FDA review of reports of rhabdomyolysis in other currently marketed statins found that the rate of reports per million U.S. prescriptions ranged from none for fluvastatin to 1.2 per million for lovastatin, the next highest being 0.8 for simvastatin, then 0·3 for atorvastatin.[4]

If the majority of the 11 U.S. postmarketing reports of rhabdomyolysis meet the case definition used in the FDA paper[4] (ie, creatine phosphokinase concentration >10 000 IU/L), as did 62% of the eight premarketing cases, and using the FDA estimate of one million prescriptions for rosuvastatin in the USA,[5] the rate of rhabdomyolysis reports for rosuvastatin is probably higher than the highest of any other currently marketed statin, predictable from preapproval trial data. Only cerivastatin, now banned, was higher at 18.1 per million.

There have been eight reported cases of acute renal failure and four of renal insufficiency in patients using rosuvastatin since marketing began. Of these 12 cases, the dose was known in 11: nine were using the 10 mg dose, the other two 40 and 80 mg.

By now, the number of reported cases of rhabdomyolysis and renal insufficiency or renal failure – 20 of which have occurred in people using 10 mg – is certain to have increased substantially from the number filed by April 13, 2004. The renal toxicity, high rate of cases of rhabdomyolysis compared with other statins, and lack of unique benefit are compelling reasons to remove rosuvastatin from the market before additional patients are injured or killed. To allow AstraZeneca to continue desperately seeking a piece of the estimated $20 billion a year statin market hardly justifies governments allowing this ultimately doomed drug to stay on the market.

Public Citizen’s Health Research Group, 1600 20th Street Northwest, Washington, DC 20009, USA

[1] Food and Drug Administration Center for Drug Evaluation and Research (CDER). Endocrinologic and Metabolic Drugs Advisory Committee Meeting, July 9, 2003. Briefing information: Crestor: indicated for the treatment of hypercholesterolemia and mixed dyslipidemia. http://www.fda.gov/ohrms/dockets /ac/03/briefing/3968b1.htm (accessed June 1, 2004).

[2] Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research Endocrinologic and Metabolic Drugs Advisory Committee. July 9, 2003, Bethesda, MD, USA. http://www.fda.gov/ohrms/dockets/ac/03/ transcripts/3968T1.htm (accessed June 1, 2004).

[3] Mele J. Crestor (ZD4522, rosuvastatin calcium) tablets: comments on efficacy. http://www.fda.gov/ohrms/dockets/ac/03/ slides/3968S1_02_FDA-Mele.ppt#8 (accessed June 10, 2004).

[4] Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Safety 2004; 13: 417-26. http:// interscience.wiley.com DOI: 10.1002/pds.977 [PubMed]

[5] Gardner A. Group seeks ban on cholesterol drug. http://www. medicinenet.com/script/main/ art.asp?articlekey=32678 (accessed June 1, 2004).