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U.S. Department of Health and Human Services

Drugs

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FDA Public Health Advisory for Crestor (rosuvastatin)

3/2/2005

Astra-Zeneca Pharmaceuticals today released a revised package insert for Crestor (rosuvastatin) (link to FDA approved labeling). The changes to the label include results from a Phase 4 pharmacokinetic study in Asian-Americans and highlight important information on the safe use of Crestor to reduce the risk for serious muscle toxicity (myopathy/rhabdomyolysis), especially at the highest approved dose of 40 mg. At this time, the FDA is also making statements about the muscle and kidney safety of Crestor based on extensive review of available information.

Background

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. These data supported the safety and efficacy of Crestor for use in lowering serum cholesterol, but also showed that Crestor, like all statins, rarely could cause serious muscle damage (myopathy and rhabdomyolysis). In the approved labeling, the FDA identified in the WARNINGS section of the product label those patients in whom more careful monitoring was warranted when prescribed Crestor. In a section titled: “Myopathy/Rhabdomyolysis”, the label 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.

Based on these concerns, from the time of original approval, 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.

Description of current changes to the Crestor label

In a pharmacokinetic study involving a diverse population of Asians residing in the United States, rosuvastatin drug levels were found to be elevated approximately 2-fold compared with a Caucasian control group. As a result of these findings, the “Dosage and Administration” section of the label now states that the 5 mg dose of Crestor should be considered as the start dose for Asian patients and any increase in dose should take into consideration the increased drug exposure in this patient population. Results of this pharmacokinetic study are further discussed under the “Clinical Pharmacology” and “Precautions” section of labeling.

The “Warnings” and “Dosage and Administration” sections of the label have been revised to more strongly emphasize the risks of myopathy, particularly at the highest approved dose of 40 mg. In order to minimize risks of myopathy and rhabdomyolysis (the most severe form of statin muscle injury), the revised label now explicitly states that the 5 mg dose is available as a start dose for those individuals who do not require aggressive cholesterol reductions or who have predisposing factors for myopathy. This includes patients taking cyclosporine, Asian patients, and patients with severe renal insufficiency. It also emphasizes that the 40 mg dose is not an appropriate start dose and should be reserved only for those patients who have not achieved their cholesterol goals with the 20 mg dose. This information is included in a bolded paragraph under the “Dosage and Administration” section that also reminds prescribers who switch patients from other statins to initiate therapy only with approved doses of Crestor and titrate according to the patient's individualized goal of therapy.

Healthcare professionals 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 organ failure that are potentially life-threatening

  • Patients should be told to promptly report to their healthcare provider signs or symptoms of muscle pain and weakness, malaise, fever, dark urine, nausea or vomiting

Review of Crestor muscle and kidney safety

Concerns have been raised about the possible increased muscle toxicity of Crestor compared to other statins on the market and about possible adverse effects on the kidney. The FDA has conducted an extensive review of Crestor data from pre-marketing and post-marketing clinical trials as well as adverse event reports submitted to the agency.

Muscle
Crestor, like all statins, has been associated with a low incidence of rhabdomyolysis (severe muscle damage). Data available to date from controlled trials, as well as post-marketing safety information, indicate that the risk of serious muscle damage is similar with Crestor compared to other marketed statins. As with all statins, some individuals taking Crestor will experience muscle side effects, most commonly mild aches and very rarely severe muscle damage. Like all drugs in this class, risks of muscle injury can be minimized by adhering to labeled warnings and precautions, carefully following dosing instructions, and instructing patients to be aware of and to report possible side effects to the physician. Finally, like all statins, Crestor should be prescribed at the lowest dose that achieves the goals of therapy (e.g., target LDL-C level).

Kidney
Various forms of kidney failure have been reported in patients taking Crestor, as well as with other statins. Renal failure due to other factors is known to occur at a higher rate in patients who are candidates for statin therapy (e.g., patients with diabetes, hypertension, atherosclerosis, heart failure). No consistent pattern of clinical presentation or of renal injury (i.e., pathology) is evident among the cases of renal failure reported to date that clearly indicate causation by Crestor or other statins.

Mild, transient proteinuria (or protein in the urine, usually from the tubules), with and without microscopic hematuria (minute amounts of blood in the urine), occurred with Crestor, as it has with other statins, in Crestor’s pre-approval trials. The frequency of occurrence of proteinuria appeared dose-related. In clinical trials with doses from 5 to 40 mg daily, this effect was not associated with renal impairment or renal failure (i.e., damage to the kidneys). It is recommended, nevertheless, that a dose reduction and an investigation into other potential causes be considered if a patient on Crestor develops unexplained, persistent proteinuria.

Ongoing controlled clinical trials of Crestor and other statins, epidemiologic studies of the safety and side effects of Crestor, and ongoing pharmacovigilance by FDA will continue to provide information on the balance of risks and benefits of Crestor and other members of this important class of drugs. This information will be made available and, as appropriate, applied to drug labeling in a timely fashion.

The current FDA-approved label can be obtained at: FDA approved labeling for Crestor