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Pharmacokinetics

• Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both C_max and AUC increased in approximate proportion to CRESTOR^® (rosuvastatin calcium) dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of CRESTOR with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration¹
• Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations¹
• Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound¹
• Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t_1/2) of rosuvastatin is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route¹
• Race: A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and C_max) in Asian subjects when compared with a Caucasian control group¹
• Gender: There were no differences in plasma concentrations of rosuvastatin between men and women¹
• Geriatric: There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years)¹
• Renal Impairment: Mild to moderate renal impairment (CL_cr ≥30 mL/min/1.73 m²) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CL_cr <30 mL/min/1.73 m²) not receiving hemodialysis compared with healthy subjects (CL_cr >80 mL/min/1.73 m²)¹
• Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function¹
• Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, C_max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C_max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function¹

Drug-Drug Interactions

• Cytochrome P450 3A4: Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent¹
• Cyclosporine: Combination increases rosuvastatin exposure. Limit CRESTOR dose to 5 mg once daily¹
• Gemfibrozil: Combination should be avoided. If used together, limit CRESTOR dose to 10 mg once daily¹
• Lopinavir/ritonavir or atazanavir/ritonavir: Combination increases rosuvastatin exposure. Limit CRESTOR dose to 10 mg once daily¹
• Coumarin anticoagulants: Combination prolongs INR. Achieve stable INR prior to starting CRESTOR. Monitor INR frequently until stable upon initiation or alteration of CRESTOR therapy¹
• Concomitant lipid-lowering therapies: Use with fibrates or lipid modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with CRESTOR¹
• Concomitant use of antacids: When taking CRESTOR with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after CRESTOR administration

Learn more about the efficacy of CRESTOR based on clinical trial data by reviewing our clinical experience.

Important Safety Information for CRESTOR Tablets

• CRESTOR is contraindicated in patients with a known hypersensitivity to any component of this product, in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels, in women who are pregnant or may become pregnant, and in nursing mothers
• Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with statins, including CRESTOR. These risks can occur at any dose level but are increased at the highest dose (40 mg)
• CRESTOR should be prescribed with caution in patients with predisposing factors for myopathy (eg, age ≥65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with CRESTOR may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, lopinavir/ritonavir, or atazanavir/ritonavir
• Therapy with CRESTOR should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever
• It is recommended that liver enzyme tests be performed before the initiation of CRESTOR and if signs or symptoms of liver injury occur. All patients treated with CRESTOR should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including CRESTOR. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with CRESTOR, promptly interrupt therapy. If an alternate etiology is not found, do not restart CRESTOR
• CRESTOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease
• CRESTOR significantly increased INR in patients receiving coumarin anticoagulants. In patients taking coumarin anticoagulants and CRESTOR concomitantly, INR should be determined before starting CRESTOR and frequently enough during early therapy to ensure that no significant alteration of INR occurs
• Dipstick-positive proteinuria and microscopic hematuria were observed among patients treated with CRESTOR. These findings were more frequent in patients taking CRESTOR 40 mg, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, dose reduction should be considered for patients on CRESTOR therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing
• Increases in HbA1c and fasting serum glucose levels have been reported with statins, including CRESTOR
• In the controlled clinical trials database, the most common adverse reactions were headache (3.7%), myalgia (3.1%), abdominal pain (2.6%), asthenia (2.5%), and nausea (2.2%)^#‡‡
• Rare postmarketing reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with statin use, including CRESTOR. These reports are generally nonserious and reversible upon statin discontinuation
• The dose range for CRESTOR is 5 mg to 40 mg orally once daily. The usual starting dose is 10 mg to 20 mg. Patients initiating CRESTOR therapy or switching from another statin should begin treatment with CRESTOR at the appropriate starting dose. After initiation or upon titration of CRESTOR, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly. CRESTOR 40 mg should be used only for those patients not achieving their LDL-C goal with 20 mg

Indications

• CRESTOR is indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, ApoB, non-HDL-C, and triglycerides, and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia and to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels
• CRESTOR is indicated to reduce the risk of myocardial infarction, stroke, and arterial revascularization procedures in patients without clinically evident coronary heart disease but with an increased risk of cardiovascular disease (CVD) based on age (men ≥50 and women ≥60), high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L, and the presence of at least one additional CVD risk factor, such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease

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CRESTOR is licensed from SHIONOGI & CO, LTD, Osaka, Japan.

CRESTOR is a registered trademark of the AstraZeneca group of companies.

©2012 AstraZeneca. All rights reserved. 1569505 3/12

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  This product information is intended for US health care professionals only.