What Risks Are Associated With High-Dose Rosuvastatin?

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What Risks Are Associated With High-Dose Rosuvastatin?


What information is available regarding the use and safety of rosuvastatin (Crestor®) 80 mg daily?

Response from Jodi H. Walker, PharmD
Adjunct Faculty, Albany College of Pharmacy, Albany, New York; Clinical Pharmacy Specialist, VA Medical Center, Bath, New York

Rosuvastatin, a hydroxy-methylglutaryl coenzyme A reductase inhibitor, is approved in doses ranging from 5 mg to 40 mg daily. Rosuvastatin is a potent statin, about twice as potent as atorvastatin, 4 times as potent as simvastatin, and at least 8 times as potent as pravastatin and lovastatin.

Dosing rosuvastatin at 80 mg exceeds the manufacturer's maximum daily dose and is not approved by the US Food and Drug Administration (FDA). This dose has been evaluated in clinical trials, however. In fact, the manufacturer initially was developing an 80-mg dose. Although rosuvastatin 80 mg monotherapy resulted in the greatest reduction of low-density lipoprotein (LDL) cholesterol (65%) compared with other studied statins, it also was associated with increased risk for muscle toxicity (eg, myopathy, rhabdomyolysis) and renal toxicity (eg, proteinuria, hematuria, increased serum creatinine).

According to preapproval documents, among patients receiving the 80-mg dose, the incidence rates of myopathy (1%) and rhabdomyolysis (0.4%) were higher than those reported in the original new drug application and labeling of approved statins. Preapproval documents also noted a high frequency of elevated creatine kinase levels associated with rosuvastatin compared with other statins. At lower recommended doses, the rate of myopathy with rosuvastatin is similar to that of other statins. The FDA ultimately denied approval of the 80-mg dose because of safety concerns and the limited additional benefit compared with the 40-mg dose. Cases of rhabdomyolysis and renal failure have been reported since marketing of rosuvastatin, including a recent case of rhabdomyolysis associated with the 80-mg dose.

Risk factors for rosuvastatin-induced myopathy and rhabdomyolysis include age 65 years or older, Asian ethnicity, hypothyroidism, renal impairment, and coadministration with cyclosporine, lopinavir/ritonavir (Kaletra®), fibrates, niacin, or gemfibrozil. General risks for statin-induced rhabdomyolysis have been proposed and include hepatic dysfunction, hypertriglyceridemia, small body frame and frailty, metabolic muscle diseases, drugs affecting statin metabolism or elimination, postoperative status, and chronic alcohol use.

Due to risk for myopathy and rhabdomyolysis, the lowest effective rosuvastatin dose should be used. A lower initial dose of 5 mg is recommended for patients of Asian ethnicity, patients with severe renal impairment, and patients taking concomitant lopinavir/ritonavir. A reduced initial dose should be considered in patients receiving fibrates or niacin; coadministration with gemfibrozil should be avoided. The 40-mg dose is only recommended for patients who have not achieved their LDL goal with 20 mg.

Choosing to prescribe rosuvastatin 80 mg is influenced by several issues: patient risk factors for rhabdomyolysis, concomitant medications, comorbid conditions, and need for close monitoring. The benefits and risks inherent in such dosing depend on the individual patient. Patients who receive any dose of rosuvastatin should be monitored closely after any dosage adjustments. All patients on rosuvastatin should be counseled to seek immediate medical attention for signs and symptoms of rhabdomyolysis, including muscle pain, muscle weakness or cramps, and dark urine. If rhabdomyolysis is suspected, the statin should be discontinued immediately and supportive measures taken.

The author wishes to acknowledge Stephanie Kohan, PharmD student, for her contributions in researching and compiling this response.

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