Worst Pills, Best Pills News article
Rosuvastatin (CRESTOR) became the sixth cholesterol lowering "statin"
drug on the U.S. market when it was approved by the Food and Drug Administration (FDA) on August 13, 2003. The other
members of the statin family are atorvastatin (LIPITOR), fluvastatin (LESCOL), lovastatin (MEVACOR), pravastatin (PRAVACHOL),
and simvastatin (ZOCOR). These drugs are only approved to be used along with a low-cholesterol diet and an exercise program
to lower cholesterol.
One of the statins, cerivastatin (BAYCOL), was removed from the
market because of at least 31 reports of fatal rhabdomyolysis, an adverse reaction involving the destruction of muscle tissue
that can lead to kidney failure (see Worst Pills, Best Pills News October 2001). We had warned patients not to
use this drug more than three years before it was removed from the market.
Rosuvastatin will be sold by AstraZeneca of Wilmington, DE under
license from Shionogi & Co., Ltd., of Osaka, Japan.
AstraZeneca originally filed its application with the FDA to market
rosuvastatin in June 2001. The application was delayed when the company halted clinical trials worldwide after reports
of kidney damage and muscle weakness (an early signal for rhabdomyolysis) in clinical trials in patients taking 80 milligrams
of the drug per day and the FDA asked AstraZeneca for more data. The company stopped development of the 80 milligram
dose because of the safety problems, and rosuvastatin will only be sold in 5, 10, 20, and 40 milligram strengths. Because
of safety concerns there will be special restrictions on the distribution of the 40 milligram strength that will be discussed
The Health Research Group made a formal presentation before the
FDA's Endocrinologic and Metabolic Drugs Advisory Committee on July 9, 2003 strongly opposing the approval of rosuvastatin because of its unique kidney toxicity.
We were also seriously concerned because of seven cases of rhabdomyolysis
that were common enough to have shown up in the pre-approval clinical trials of rosuvastatin in which the 80 milligram dose
was used. Not one case of rhabdomyolysis appeared in any of the pre-approval studies of the previously approved
statins, including cerivastatin, which was removed from the market because of rhabdomyolysis.
As we said in our testimony before the advisory committee, a major
factor that distinguishes rosuvastatin from the other five statins remaining on the market is the drug's potential to cause
kidney toxicity. In the FDA review documents posted on the agency's web site before the Endocrinologic and Metabolic
Drugs Advisory Committee it was noted "In contrast to currently approved statins, rosuvastatin was also associated with renal
[kidney] findings not previously reported with other statins."
A number of patients taking primarily the 80 and 40 milligram doses
of rosuvastatin had an increased frequency of persistent protein in the urine (proteinuria) and blood in the urine (hematuria),
that in some subjects was also associated with another abnormal test result that is an early signal for kidney toxicity known
as the serum creatinine level. The FDA documents pointed out that there were two cases of kidney failure and one case
of kidney insufficiency with 80 milligrams of rosuvastatin in which these patients also had experienced both protein and blood
in the urine.
An FDA medical officer reviewing rosuvastatin had sobering comments
on the cases of kidney problems with the drug:
These three cases of renal insufficiency of unknown etiology are 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
[death of cells]. All cases occurred at the 80 mg dose which was also associated with the greatest number of patients with
abnormal renal findings in these clinical trials. Proteinuria and hematuria could be potentially managed with regular urinalysis
screening. However, if they 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.
AstraZeneca attempted to "spin" the drug's potential for causing
elevated protein levels in the urine by claiming that it was due to a previously unobserved effect of the statin family
of drugs. However, the research submitted by AstraZeneca to the FDA did not show a similar degree urine protein elevation
with any of the other statins.
The Endocrinologic and Metabolic Drugs Advisory Committee recommended
that kidney monitoring be required for patients taking 40 milligrams of rosuvastatin per day. The FDA failed to take
this advice, rather, the agency approved this puzzling statement in the Laboratory Tests section of the drug's professional
product labeling or package insert:
In the rosuvastatin clinical trial program, dipstick-positive proteinuria
and microscopic hematuria were observed among rosuvastatin treated patients, predominantly in patients dosed above the recommended
dose range (i.e., 80 mg). However, this finding was more frequent in patients taking rosuvastatin 40 mg, when compared to
lower doses of rosuvastatin or comparator statins, though it was generally transient and was not associated with worsening
renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients
on rosuvastatin 40 mg therapy with unexplained persistent proteinuria during routine urinalysis testing.
The problem with this statement is that it is very unlikely that
the average patient would routinely receive urine testing for protein. National guidelines only recommend the periodic
urine testing of people without symptoms who have diabetes or for pregnant women. At a minimum the FDA should have required
routine urine testing for all dosages of rosuvastatin.
Any elevation of protein in the urine beyond a trace is abnormal
and is a possible signal of more serious kidney problems, even more so if there is also blood in the urine.
A popular buzz word frequently used by the FDA these days is Risk
Management B assessing public health risks, analyzing methods for reducing them, and taking appropriate action. The
FDA's Risk Management strategy for the safety problems associated rosuvastatin can hardly be called "appropriate." The
40 milligram tablet will not be stocked in retail pharmacies and the pharmacy would need to go through a wholesaler to obtain
the 40 milligram tablets. This would take an extra day before the tablets arrived at the pharmacy. Somehow the
FDA believes that "These steps will help to ensure that the 40-mg dose is available only to patients who truly need this dose."
To easily beat this restriction, there is nothing to prevent a physician from writing a prescription for 20 milligram tablets
and instructing the patient to take two tablets of rosuvastatin daily.
Clearly, the only "appropriate" and safe Risk Management strategy for rosuvastatin would have been not to have approved the
drug in the first place.
Rosuvastatin's professional labeling also carries warnings about
elevated liver enzymes, an early signal for possible liver toxicity, and muscle pain and weakness that may be precursors to
rhabdomyolysis. These warnings appear in the labeling for all statin drugs:
It is recommended that liver function tests
be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g.,
Rare cases of rhabdomyolysis with acute renal failure secondary
to myoglobinuria [a protein from muscle] have been reported with rosuvastatin and with other drugs in this class.
The professional product labeling goes on to instruct physicians
to tell patients "... to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by
malaise or fever."
The risk of muscle damage leading to rhabdomyolysis during treatment
with rosuvastatin may be increased when it is used together with other cholesterol lowering drugs and cyclosporine (NEORAL,
SANDIMMUNE), a drug used after transplantation to prevent organ rejection.
A single rosuvastatin dose given to healthy volunteers on the cholesterol
lowering drug gemfibrozil (LOPID) resulted in a significant increase in the amount of rosuvastatin in the body. There is a
bold statement in the Warnings section of rosuvastatin's labeling stating that "Combination therapy
with rosuvastatin and gemfibrozil should generally be avoided." The risk of muscle problems possibly leading
to rhabdomyolysis is also increased when niacin is used to lower cholesterol in combination with rosuvastatin.
When rosuvastatin was given together with cyclosporine in heart
transplant patients, the amount of rosuvastatin increased significantly in the blood compared with healthy volunteers. This
increase is considered to be clinically significant.
When rosuvastatin was given to patients on stable warfarin (COUMADIN)
treatment to prevent blood clots, there was a clinically significant rise in the International Normalized Ratio (INR), the
laboratory test used to monitor warfarin therapy that can increase the risk of bleeding.
A number of factors went into our decision to list rosuvastatin
as a DO NOT USE drug:
1. Rosuvastatin joins atorvastatin and fluvastatin as the
statins that have not demonstrated a health benefit to the patients that use them in terms of reducing the serious cardiovascular
consequences of high cholesterol such as a first or second heart attack or stroke. Lovastatin, pravastatin, and simvastatin
have shown such benefits to patients in addition to their cholesterol lowering properties and this is reflected in the professional
product labels and advertising for these drugs.
The only reliable, valid indicator that consumers can use that a
drug has a demonstrated health benefit is if that information is contained in the drug's FDA approved product labeling.
Advertising claims for drugs can not be made unless research has been submitted to and approved by the FDA that the drug will
actually do what a manufacturer claims it will do.
2. Rosuvastatin causes abnormal elevations in urine protein
and blood that are signals for serious kidney toxicity; other statins are not associated with this risk of kidney toxicity.
3. Rosuvastatin is the only statin that has shown life-threatening
rhabdomyolysis in pre-approval clinical trials.
In summary, rosuvastatin has no proven health benefit as discussed
above, it can cause potentially serious kidney toxicity that is not seen with the other statins, it is the only statin that
caused rhabdomyolysis, a life-threatening adverse drug reaction, in pre-approval clinical trials, and there are already three
statins on the market that are safer than rosuvastatin and have demonstrated a health benefit to patients.
What You Can Do
There is no medical reason for you to be taking rosuvastatin when
there are three safer and more effective statins, in terms of reducing cardiovascular events, on the market.