Do Not Use! Rosuvastatin (Crestor)

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Do Not Use! Rosuvastatin (Crestor) - A New But More Dangerous Cholesterol

Lowering 'Statin' Drug

Worst Pills, Best Pills News article October, 2003

 

NOTE: Public Citizen is posting this article free of charge because of the

serious risks seen in clinical trials with this drug.

 

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 further below.

 

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., semiannually) thereafter.

 

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.

 

 

 

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