NEWSLETTER 11: BAD CRESTOR

Crestor Rhabdomyolysis

Rhabdomyolysis is a life-threatening muscle deterioration that is associated with statin type of cholesterol lowering medication like Crestor. AstraZeneca's NDA (new drug application) with the FDA for Crestor was initially delayed when the company halted clinical trials worldwide after reports of kidney damage, death and muscle weakness (an early signal for rhabdomyolysis) in clinical trials in patients taking 80 milligrams of Crestor per day. Crestor labeling includes warnings about the potential for muscle and kidney problems, including rhabdomyolysis, but warning labels arguably may not be adequate and sufficient enough to convey the seriousness of the severe side effects that can occur from Crestor use. Crestor is the only statin that is known to have caused rhabdomyolysis in pre-approval clinical trials. 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 along with the cholesterol-lowering drug gemfibrozil (LOPID) resulted in a significant increase in the amount of rosuvastatin in the body. There is a bolded 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. Crestor, a member of a class of cholesterol-lowering drugs commonly referred to as "statins", was approved in the U.S. in August 2003, and based on review of an extensive clinical database involving approximately 12,000 patients. "Myopathy/Rhabdomyolysis" increased risk in: increased age, hypothyroidism; renal insufficiency. Physicians are warned to prescribe Crestor with caution in these patients, particularly at higher doses, as the risk of myopathy increases with higher drug levels. In addition, the U.S. approved labeling for Crestor states that increased rosuvastatin drug levels were observed in certain sub-populations of patients (ie: subgroups of Asians, patients concomitantly using cyclosporine and gemfibrozil), conferring increased risk of myopathy. Because of these findings, the FDA required Astra-Zeneca to make available in the U.S. a 5-mg dose that could be used in patients requiring less aggressive cholesterol-lowering, or who were taking concurrent cyclosporine. The maximum recommended dose in the FDA-approved label is limited to 10-mg daily in patients with severe renal impairment or who are also taking gemfibrozil. To date, seven patients using Crestor (rosuvastatin) are known to have developed a deteriorative muscle condition known as rhabdomyolysis, and nine others have suffered kidney damage or failure. Even the death of a 39 year old woman isn't enough for the FDA to ban Crestor.

Some people claim that Crestor has dangerous side effects such as proteinuria (protein in the urine) and rhabdomyolysis, (a dangerous condition where the muscles break down and release toxic chemicals into the bloodstream that hurt the kidneys). For Crestor, there were about 13 reports of rhabdomyolysis for every million prescriptions filled, Public Citizen estimated. That rate was 6.2 times higher than the rates for all other statins combined.

Healthcare professionals prescribing Crestor are reminded of the following key safety messages from the Crestor label: start doses and maintenance doses of drug should be based on individual cholesterol goals and apparent risks for side-effects; all patients should be informed that statins can cause muscle injury, which in rare, severe cases, can cause kidney damage and other organ failure that are potentially life-threatening; and patients should be told to promptly report to their physician signs or symptoms of muscle pain and weakness, malaise, fever, dark urine, nausea, or vomiting.

The original New Drug Application for Crestor was submitted on June 26, 2001. An approvable action was taken by the agency on May 31, 2002, based on safety concerns arising out of the initial review regarding muscle and kidney. More specifically, several cases of severe myopathy or rhabdomyolysis occurred in patients treated with 80 milligrams daily, the highest dose initially proposed.

There were no cases seen at 40 milligrams, although patient exposures at 40 milligrams were far fewer. Based on this primary safety concern and the marginal incremental LDL lowering seen with the step from 40 to 80 milligrams, the agency concluded that 80 milligrams should not be approved. In response to the FDA request, the sponsor has studied the myopathic risk associated with Crestor use in a very large premarketing patient exposure, indeed, by far the largest of any statin brought before the FDA. The sponsor and the FDA medical officer, Dr. Lubas, will presented data that suggests that the risk of myopathy with Crestor relative to LDL-lowering efficacy is, at the very least, no greater than that with the other marketed members of the statin class. The critical importance of this issue in the evaluation of the safety of this drug however, is the emergent profile for the 80-milligram dose did not meet the objectives for the favorable benefit-risk profile for the general population. So, in March of 2002, AstraZeneca and the Review Division agreed to suspend further development of the rosuvastatin 80-milligram dose for the general population, and all patients who were receiving the 80-milligram daily dose had their dose reduced to 40-milligram daily. (See: http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3968T1.doc for more details).

Of note are CK elevations greater than ten times the upper limit of normal occurring 0.2 to 0.4 percent at rosuvastatin doses from 5 to 40 but increased to 1.9 percent at the 80-milligram dose. No wonder they didn’t approve Crestor 80mgm.

Myopathy, which is CK elevations greater than ten times the upper limit of normal plus the associated muscle symptoms, was seen with Crestor. The eleven cases of possibly treatment-related myopathy at the 80-milligram gives a frequency of 0.7 percent at this dose.

Rhabdomyolysis cases are defined as those patients with myopathy who required hospitalization to receive intravenous fluids. "AstraZeneca confirms that a death possibly attributed to rhabdomyolysis associated with Crestor has been reported. The case details are complex, with clinical features more consistent with neuroleptic malignant syndrome, a condition seen with antipsychotic agents." Muscle problems have been associated with all statins used to tackle high cholesterol and AstraZeneca noted more than 14 million prescriptions had been written for its medicine worldwide. This is the first suspected fatal case of rhabdomyolysis associated with Crestor. According to a statement of Sidney M. Wolfe, PhD, Director, Public Citizen's Health Research Group 52 U.S. cases of life-threatening muscle damage (rhabdomyolysis) were already reported to the FDA.

AZ's spin on rhabdomyolysis is that it only occurred in the 80 mgm dose that was not approved. In the approved dose between 5 and 40 mgm they feel it is safe.

And then there's the kidney thing. Crestor is the first statin to be associated with protein and blood in the urine. AZ's spin on it is that it is an unrecognized class effect that is present with all the statins if you use a high enough dose. Also that it is not associated with "kidney disease" but merely a normal response to having that much statin in the distal convoluted tubule. This has never been seen with any other statin. When doctors see this they are going to order expensive tests and consults that will add cost and harm patients.

A new analysis of post-marketing safety reports suggests that patients using Crestor (rosuvastatin) are more likely to develop serious side effects than patients taking Lipitor (atorvastatin), Zocor (simvastatin), or Pravachol (pravastatin). According to a May 2005 study done at Tufts University, patients taking Crestor are eight times more likely to develop rhabdomyolysis, nephropathy, renal failure or proteinuria than patients taking Pravachol, and 6.5 times more likely to develop those complications than patients taking Lipitor. The study, published in Circulation, an American Heart Association journal, reported that the adverse event risk was 2.2 fold higher for Crestor versus Zocor.

The study was conducted by Dr. Richard H. Karas, Director for the Center for Preventative Cardiology at Tufts University and was an analysis of reports of adverse events experienced by people taking the statin drugs Crestor, Pravachol, or Lipitor. The data was broken down several ways but overall, Crestor was associated with many more adverse event reports than Pravachol or Lipitor, possibly because Crestor is a super-stain and more potent than other statins, even at its lowest dosage.

Reasons not to use Crestor:

1. Problems with patients that have hypothyroidism.
2. Problems with patients > 65.
3. Problems with patients with chronic renal insufficiency.
4. Crestor is the only statin associated with hematuria and proteinuria.
5. Asians have twice the Crestor level as others.
6. It is too new to have hard core outcomes data like its competitor Zocor proving that it not only lowers the secondary endpoint, hyperlipidemia, but that it actually turns out to prevent heart attacks, stokes and cause people to live longer.

It is appropriate to consider a Crestor law suit if a patient on Crestor experiences any of the following Adverse Events:

1. A muscle pain problem.
2. Muscle Inflammation
3. Muscle Soreness
4. Muscle Tenderness
5. Malaise
6. Fever
7. Dark Urine
8. Nausea
9. Vomiting
10. Rhabdomyolysis requiring hospilization
11. Elevated CK blood test
12. Drug-induced hepatitis diagnosed with elevated blood test (LFTs: AST & ALT)
13. Death
14. Blood in urine
15. Protein in urine
16. Weak kidneys or kidney failure requiring dialysis
17. Heart attack or stroke as Crestor, unlike Zocor, is not proven to prevent these illnesses and prolong life.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Expert Medical Witness, ExpertMD
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
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