Astra-Zeneca Pharmaceuticals today released a revised package insert for Crestor (rosuvastatin) for use in the 22 member states of the European Union (EU). The changes to the European labeling are in response to postmarketing spontaneous adverse event reports in patients receiving Crestor and highlight certain patient populations who may be at an increased risk for serious muscle toxicity (myopathy) associated with Crestor use, especially at the highest approved dose of 40 mg. These risk factors and many of the recommendations for how to minimize the risk of myopathy are already captured in the FDA approved labeling for Crestor in the U.S. FDA is alerting physicians to the need to carefully read the Crestor product label and follow the recommendations for starting doses, dose adjustments, and maximum daily doses to minimize the risk of myopathy in individual patients.

Crestor, a member of a class of cholesterol-lowering drugs commonly referred to as ?statins?, was approved in the U.S. in August 2003, based on review of an extensive clinical database involving approximately 12,000 patients. At that time, the FDA identified in the WARNINGS section of the product label those patients whose increased baseline risk for myopathy warranted more careful monitoring when prescribed Crestor. The U.S. approved labeling included a specific section titled, ?Myopathy/Rhabdomyolysis?, which states that patients who are of advanced age (? 65 years), have hypothyroidism, and/or renal insufficiency should be considered to have a greater risk for developing myopathy while receiving a statin. 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 (e.g., 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.

FDA has received reports of rhabdomyolysis in association with Crestor, as it has with other drugs in the statin class. In ongoing fashion, we are evaluating these reports of adverse muscle effects with regard to clinical severity and apparent relationship to the drug. FDA is comparing the frequency of reporting of muscle injury with Crestor to that with other statins, given differences in prescribing rates for the different drugs. Pending the evaluation of the recent Crestor safety experience, FDA is not proposing to change the US labeling for Crestor, but does want to re-emphasize to physicians to the importance of carefully following the recommendations in the current product label. Analysis of accumulating safety data in the U.S. and worldwide will be considered in any future labeling changes for Crestor, and to make recommendations on risk management plans for Crestor.

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 current FDA-approved label can be obtained at http://www.fda.gov/cder/foi/label/2003/21366_crestor_lbl.pdf
 

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