WARNINGS AND PRECAUTIONS
Skeletal Muscle Effects
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, 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 (e.g., 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, orlopinavir/ritonavir. [ see Dosage and Administration (2) and Drug Interactions (7)].
CRESTOR therapy should be discontinued if markedly elevated creatinine kinase levels occur or myopathy is diagnosed or suspected. CRESTOR therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
Liver Enzyme Abnormalities and Monitoring
It is recommended that liver enzyme tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter.
Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including CRESTOR. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to CRESTOR therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.
In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking CRESTOR versus 0.5% of patients treated with placebo.
Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of CRESTOR is recommended.
CRESTOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [ see Clinical Pharmacology ]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of CRESTOR. [ see Contraindications (4)]
Concomitant Coumarin Anticoagulants
Caution should be exercised when anticoagulants are given in conjunction with CRESTOR because of its potentiation of the effect of coumarin-type anti-coagulants in prolonging the prothrombin time/INR. 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. [ see Drug Interactions ]
Proteinuria and Hematuria
In the CRESTOR clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among CRESTOR treated patients. These findings were more frequent in patients taking CRESTOR 40 mg, when compared to lower doses of CRESTOR or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on CRESTOR therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.
Although clinical studies have shown that CRESTOR alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if CRESTOR is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.
USE IN SPECIFIC POPULATIONS
Teratogenic effects: Pregnancy Category X.
CRESTOR is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy. [ see Contraindications (4)]
There are no adequate and well-controlled studies of CRESTOR in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Rosuvastatin crosses the placenta in rats and rabbits. In rats, CRESTOR was not teratogenic at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10-12 times the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight among female pups, and delayed ossification. In rabbits, pup viability decreased and maternal mortality increased at doses equivalent to the human dose of 40 mg/day. [ see Nonclinical Toxicology (13.2)]
CRESTOR may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking CRESTOR, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.
It is not known whether rosuvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of rosuvastatin are three times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require CRESTOR treatment should be advised not to nurse their infants. [ see Contraindications (4)]
The safety and effectiveness of CRESTOR in pediatric patients have not been established.
Treatment experience with CRESTOR in a pediatric population is limited to 8 patients with homozygous FH. None of these patients was below 8 years of age.
In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with heterozygous FH received single and multiple oral doses of CRESTOR. Both Cmax and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses.
Of the 10,275 patients in clinical studies with CRESTOR, 3,159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Elderly patients are at higher risk of myopathy and CRESTOR should be prescribed with caution in the elderly. [ see Warnings and Precautions, (5.1) and Clinical Pharmacology,]
Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr ≥ 30 mL/min/1.73 m2); however, exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment who are not receiving hemodialysis. CRESTOR dosing should be adjusted in patients with severe renal impairment (CLcr < 30 mL/min/1.73 m2) not requiring hemodialysis. [ see Dosage and Administration (2.7) and Warnings and Precautions (5.1) and Clinical Pharmacology ].
CRESTOR is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; CRESTOR should be used with caution in these patients. [ see Contraindications (4) and Warning and Precautions (5.2) and Clinical Pharmacology ].
Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. CRESTOR dosage should be adjusted in Asian patients. [ see Dosage and Administration (2.4) and Clinical Pharmacology ]