CRESTOR- rosuvastatin calcium tablet, film coated

CRESTOR by

Drug Labeling and Warnings

CRESTOR by is a Prescription medication manufactured, distributed, or labeled by Cardinal Health. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    1.1 Hyperlipidemia and Mixed Dyslipidemia

    CRESTOR is indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL‑C, and triglycerides and to increase HDL‑C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.

    Pediatric Patients 10 to 17 years of age with Heterozygous Familial Hypercholesterolemia (HeFH)

    Adjunct to diet to reduce Total‑C, LDL‑C and ApoB levels in adolescent boys and girls, who are at least one year post-menarche, 10‑17 years of age with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL‑C > 190 mg/dL or > 160 mg/dL and there is a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors.

    1.2 Hypertriglyceridemia

    CRESTOR is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

    1.3 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

    CRESTOR is indicated as an adjunct to diet for the treatment of patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).

    1.4 Homozygous Familial Hypercholesterolemia

    CRESTOR is indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL‑C, Total‑C, and ApoB in adult patients with homozygous familial hypercholesterolemia.

    1.5 Slowing of the Progression of Atherosclerosis

    CRESTOR is indicated as adjunctive therapy to diet 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.

    1.6 Primary Prevention of Cardiovascular Disease

    In individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age ≥ 50 years old in men and ≥ 60 years old in women, hsCRP ≥ 2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL‑C, smoking, or a family history of premature coronary heart disease, CRESTOR is indicated to:

    • reduce the risk of stroke
    • reduce the risk of myocardial infarction
    • reduce the risk of arterial revascularization procedures

    1.7 Limitations of Use

    CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 General Dosing Information

    The dose range for CRESTOR is 5 to 40 mg orally once daily. The usual starting dose is 10‑20 mg.

    CRESTOR can be administered as a single dose at any time of day, with or without food. The tablet should be swallowed whole.

    When initiating CRESTOR therapy or switching from another HMG‑CoA reductase inhibitor therapy, the appropriate CRESTOR starting dose should first be utilized, and only then titrated according to the patient’s response and individualized goal of therapy.

    After initiation or upon titration of CRESTOR, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.

    The 40 mg dose of CRESTOR should be used only for those patients who have not achieved their LDL‑C goal utilizing the 20 mg dose [seeWarnings and Precautions (5.1)].

    2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age)

    The usual dose range of CRESTOR is 5‑20 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [seeClinical Pharmacology (12) and Indications and Usage (1.2)]. Adjustments should be made at intervals of 4 weeks or more.

    2.3 Homozygous Familial Hypercholesterolemia

    The recommended starting dose of CRESTOR is 20 mg once daily. Response to therapy should be estimated from preapheresis LDL‑C levels.

    2.4 Dosing in Asian Patients

    In Asian patients, consider initiation of CRESTOR therapy with 5 mg once daily due to increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg/day. [seeUse in Specific Populations (8.8) andClinical Pharmacology (12.3)].

    2.5 Use with Concomitant Therapy

    Patients taking cyclosporine

    The dose of CRESTOR should not exceed 5 mg once daily [see Warnings and Precautions (5.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

    Patients taking gemfibrozil

    Initiate CRESTOR therapy with 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once daily [seeWarnings and Precautions (5.1) and Drug Interactions (7.2), and Clinical Pharmacology (12.3)].

    Patients taking atazanavir and ritonavir, lopinavir and ritonavir, or simeprevir

    Initiate CRESTOR therapy with 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once daily [seeWarnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

    2.6 Dosing in Patients with Severe Renal Impairment

    For patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not on hemodialysis, dosing of CRESTOR should be started at 5 mg once daily and not exceed 10 mg once daily [seeUse in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

  • 3 DOSAGE FORMS AND STRENGTHS

    5 mg: Yellow, round, biconvex, coated tablets. Debossed “CRESTOR” and “5” on one side of the tablet.

    10 mg: Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side of the tablet.

    20 mg: Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20” on one side of the tablet.

    40 mg: Pink, oval, biconvex, coated tablets. Debossed “CRESTOR” on one side and “40” on the other side of the tablet.

  • 4 CONTRAINDICATIONS

    CRESTOR is contraindicated in the following conditions:

    • Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with CRESTOR [seeAdverse Reactions (6.1)].
    • Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [seeWarnings and Precautions (5.2)].
    • Women who are pregnant or may become pregnant. Because HMG‑CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, CRESTOR may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy [seeUse in Specific Populations (8.1) and Nonclinical Toxicology (13.2)].
    • Nursing mothers. Because another drug in this class passes into breast milk, and because HMG‑CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require CRESTOR treatment should be advised not to nurse their infants [seeUse in Specific Populations (8.3)].
  • 5 WARNINGS AND PRECAUTIONS

    5.1 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, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir [seeDosage and Administration (2) and Drug Interactions (7)]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing CRESTOR with colchicine [see Drug Interactions (7.7)].

    CRESTOR therapy should be discontinued if markedly elevated creatine 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).

    There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

    All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing CRESTOR.

    5.2 Liver Enzyme Abnormalities

    It is recommended that liver enzyme tests be performed before the initiation of CRESTOR, and if signs or symptoms of liver injury occur.

    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.

    There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. 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 [seeClinical Pharmacology (12.3)]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of CRESTOR [see Contraindications (4)].

    5.3 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 anticoagulants 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 [seeDrug Interactions (7.4)].

    5.4 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.

    5.5 Endocrine Effects

    Increases in HbA1c and fasting serum glucose levels have been reported with HMG‑CoA reductase inhibitors, including CRESTOR. Based on clinical trial data with CRESTOR, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [seeAdverse Reactions (6.1)].

    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.

  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are discussed in greater detail in other sections of the label:

    In the CRESTOR controlled clinical trials database (placebo or active-controlled) of 5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:

    • myalgia
    • abdominal pain
    • nausea

    The most commonly reported adverse reactions (incidence ≥ 2%) in the CRESTOR controlled clinical trial database of 5394 patients were:

    • headache
    • myalgia
    • abdominal pain
    • asthenia
    • nausea

    6.1 Clinical Studies Experience

    Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

    Adverse reactions reported in ≥ 2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.

    •   Table . Adverse Reactions1 Reported in ≥ 2% of Patients Treated with CRESTOR and > Placebo in Placebo‑Controlled Trials (% of Patients)

    Adverse Reactions

    CRESTOR

    5 mg

    N=291

    CRESTOR

    10 mg

    N=283

    CRESTOR

    20 mg

    N=64

    CRESTOR

    40 mg

    N=106

    Total CRESTOR

    5 mg‑40 mg

    N=744

    Placebo

    N=382

    Headache

    5.5

    4.9

    3.1

    8.5

    5.5

    5.0

    Nausea

    3.8

    3.5

    6.3

    0

    3.4

    3.1

    Myalgia

    3.1

    2.1

    6.3

    1.9

    2.8

    1.3

    Asthenia

    2.4

    3.2

    4.7

    0.9

    2.7

    2.6

    Constipation

    2.1

    2.1

    4.7

    2.8

    2.4

    2.4

    Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [seeWarnings and Precautions (5.4)]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.

    In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with CRESTOR versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea [seeClinical Studies (14.7)].

    Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 2.

    •   Table . Adverse Reactions1 Reported in ≥2% of Patients Treated with CRESTOR and > Placebo in the METEOR Trial (% of Patients)
    Adverse ReactionsCRESTOR 40 mg
    N=700    		Placebo
    N=281
  • * Frequency recorded as abnormal laboratory value.
    		•

    Myalgia

    12.7

    12.1

    Arthralgia

    10.1

    7.1

    Headache

    6.4

    5.3

    Dizziness

    4.0

    2.8

    Increased CPK

    2.6

    0.7

    Abdominal pain

    2.4

    1.8

    ALT >3x ULN*

    2.2

    0.7

    In the JUPITER study, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.

    In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients [seeWarnings and Precautions (5.5) and Clinical Studies (14.8)].

    Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 3.

    •   Table . Adverse Reactions1 Reported in ≥ 2% of Patients Treated with CRESTOR and > Placebo in the JUPITER Trial (% of Patients)

    Adverse Reactions

    CRESTOR 20 mg

    N=8901

    Placebo

    N=8901

    Myalgia

    7.6

    6.6

    Arthralgia

    3.8

    3.2

    Constipation

    3.3

    3.0

    Diabetes mellitus

    2.8

    2.3

    Nausea

    2.4

    2.3

    6.2 Pediatric patients 10 to 17 years of age

    In a 12-week controlled study in boys and postmenarchal girls, the safety and tolerability profile of CRESTOR 5 to 20 mg daily was generally similar to that of placebo [seeClinical Studies (14.6) and Use in Specific Populations, Pediatric Use (8.4)].

    However, elevations in serum creatine phosphokinase (CK) > 10 x ULN were observed more frequently in rosuvastatin compared with placebo-treated children. Four of 130 (3%) children treated with rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK >10 x ULN, compared to 0 of 46 children on placebo.

    6.3 Postmarketing Experience

    The following adverse reactions have been identified during postapproval use of CRESTOR: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy and gynecomastia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].

    There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

  • 7 DRUG INTERACTIONS

    7.1 Cyclosporine

    Cyclosporine increased rosuvastatin exposure (AUC) 7‑fold. Therefore, in patients taking cyclosporine, the dose of CRESTOR should not exceed 5 mg once daily [seeDosage and Administration (2.5), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

    7.2 Gemfibrozil

    Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with CRESTOR and gemfibrozil should be avoided. If used together, the dose of CRESTOR should not exceed 10 mg once daily [seeClinical Pharmacology (12.3)].

    7.3 Protease Inhibitors

    Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase rosuvastatin exposure (AUC) up to threefold [see Table 4 –Clinical Pharmacology (12.3)]. For these protease inhibitors, the dose of CRESTOR should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are HIV-1 protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors [seeDosage and Administration (2.5),Warnings and Precautions (5.1) andClinical Pharmacology (12.3)].

    7.4 Coumarin Anticoagulants

    CRESTOR significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with CRESTOR. 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 [seeWarnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

    7.5 Niacin

    The risk of skeletal muscle effects may be enhanced when CRESTOR is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with CRESTOR [seeWarnings and Precautions (5.1)].

    7.6 Fenofibrate

    When CRESTOR was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with CRESTOR [seeWarnings and Precautions (5.1) andClinical Pharmacology (12.3)].

    7.7 Colchicine

    Cases of myopathy, including rhabdomyolysis, have been reported with HMG‑CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing CRESTOR with colchicine [seeWarnings and Precautions (5.1)].

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    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 [seeContraindications (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-fourfold 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 [seeNonclinical 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.

    8.3 Nursing Mothers

    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 [seeContraindications (4)].

    8.4 Pediatric Use

    The safety and effectiveness of CRESTOR in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial of 12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg, 10 mg, and 20 mg daily CRESTOR had an adverse experience profile generally similar to that of patients treated with placebo [seeAdverse Reactions (6.2)]. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. There was no detectable effect of CRESTOR on growth, weight, BMI (body mass index), or sexual maturation [seeClinical Studies (14.5)] in pediatric patients (10 to 17 years of age). Adolescent females should be counseled on appropriate contraceptive methods while on CRESTOR therapy [seeUse in Specific Populations (8.1)]. CRESTOR has not been studied in controlled clinical trials involving prepubertal patients or patients younger than 10 years of age. Doses of CRESTOR greater than 20  mg have not been studied in the pediatric population.

    In children and adolescents with homozygous familial hypercholesterolemia experience is limited to eight patients (aged 8 years and above).

    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.

    8.5 Geriatric Use

    Of the 10,275 patients in clinical studies with CRESTOR, 3159 (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 [seeWarnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    8.6 Renal Impairment

    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 [seeDosage and Administration (2.6), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    8.7 Hepatic Impairment

    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 [seeContraindications (4), Warning and Precautions (5.2), andClinical Pharmacology (12.3)].

    8.8 Asian Patients

    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 [seeDosage and Administration (2.4) and Clinical Pharmacology (12.3)].

  • 10 OVERDOSAGE

    There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.

  • 11 DESCRIPTION

    CRESTOR (rosuvastatin calcium) is a synthetic lipid-lowering agent for oral administration.

    The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula:

    strucural formula

    The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca and the molecular weight is 1001.14. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of  0.13 at pH of 7.0.

    CRESTOR Tablets for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the following inactive ingredients: Each tablet contains: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide NF.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    CRESTOR is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3‑hydroxy‑3‑methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

    12.3 Pharmacokinetics

    • Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to CRESTOR 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 administration.
    • 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 concentrations.
    • 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 compound.
    • Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t1/2) 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 route.
    • 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 Cmax) in Asian subjects when compared with a Caucasian control group.
    • Gender: There were no differences in plasma concentrations of rosuvastatin between men and women.
    • Geriatric: There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).
    • Renal Impairment: Mild to moderate renal impairment (CLcr ≥ 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 (CLcr < 30 mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects (CLcr > 80 mL/min/1.73 m2).
    • Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.
    • Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased.
    •   In patients with Child‑Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child‑Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

    Drug-Drug Interactions:

    Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent.

    Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of CRESTOR with medications that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy [see Dosage and Administration (2.5)]. It is recommended that prescribers consult the relevant product information when considering administration of such products together with CRESTOR.

    Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure
  • * Single dose unless otherwise noted.
    		•

    Coadministered drug and dosing regimen

    Rosuvastatin

    Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0

    Dose (mg)*

    Change in AUC

    Change in Cmax

    Cyclosporine – stable dose required (75 mg – 200 mg BID)

    10 mg QD for 10 days

    7.1
    •   11

    Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days

    10 mg

    3.1
    •   7

    Simeprevir 150 mg QD, 7 days

    10 mg, single dose

    2.8
    (2.3-3.4)
    •   3.2
    •   (2.6-3.9)

    Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days

    20 mg QD for 7 days

    2.1

    (1.7-2.6)
    •   5
    •   (3.4-6.4)

    Gemfibrozil 600 mg BID for 7 days

    80 mg

    1.9
    (1.6-2.2)
    •   2.2
    •   (1.8-2.7)

    Eltrombopag 75 mg QD, 5 days

    10 mg

    1.6

    (1.4-1.7)
    •   2
    •   (1.8-2.3)

    Darunavir 600 mg/ritonavir 100 mg BID, 7 days

    10 mg QD for 7 days

    1.5

    (1.0-2.1)

    2.4

    (1.6-3.6)

    Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days

    10 mg

    1.4

    (1.2-1.6)

    2.2

    (1.8-2.7)

    Dronedarone 400 mg BID

    10 mg

    1.4

    Itraconazole 200 mg QD, 5 days

    10 mg or 80 mg

    1.4

    (1.2-1.6)

    1.3

    (1.1-1.4)
    •   1.4
    •   (1.2-1.5)
    •   1.2
    •   (0.9-1.4)

    Ezetimibe 10 mg QD, 14 days

    10 mg QD for 14 days
    •   1.2
    •   (0.9-1.6)

    1.2

    (0.8-1.6)

    Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days

    10 mg

    1.1
    •   1.5

    Fenofibrate 67 mg TID for 7 days

    10 mg

    ↔

    1.2

    (1.1-1.3)

    Rifampicin 450 mg QD, 7 days

    20 mg

    ↔

    Aluminum & magnesium hydroxide combination antacid

    Administered simultaneously
    Administered 2 hours apart

    40 mg
    40 mg

    0.5

    (0.4-0.5)

    0.8

    (0.7-0.9)
    •   0.5
    •   (0.4-0.6)
    •   0.8
    •   (0.7-1.0)

    Ketoconazole 200 mg BID for 7 days

    80 mg

    1.0

    (0.8-1.2)

    1.0

    (0.7-1.3)

    Fluconazole 200 mg QD for 11 days

    80 mg

    1.1

    (1.0-1.3)

    1.1

    (0.9-1.4)

    Erythromycin 500 mg QID for 7 days

    80 mg

    0.8

    (0.7-0.9)

    0.7

    (0.5-0.9)
    Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure To Other Drugs
    Rosuvastatin Dosage RegimenCoadministered Drug
    Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0
    Name and DoseChange in AUCChange in Cmax
  • * Clinically significant pharmacodynamic effects [seeWarnings and Precautions (5.3)]
    		•

    40 mg QD for 10 days

    Warfarin*

    25 mg single dose

    R- Warfarin 1.0

    (1.0-1.1)

    S-Warfarin 1.1

    (1.0-1.1)

    R-Warfarin 1.0

    (0.9-1.0)

    S-Warfarin 1.0

    (0.9-1.1)

    40 mg QD for 12 days

    Digoxin

    0.5 mg single dose

    1.0

    (0.9-1.2)

    1.0

    (0.9-1.2)

    40 mg QD for 28 days

    Oral Contraceptive

    (ethinyl estradiol 0.035 mg & norgestrel 0.180, 0.215 and 0.250 mg) QD for 21 Days

    EE 1.3

    (1.2-1.3)

    NG 1.3

    (1.3-1.4)

    EE 1.3

    (1.2-1.3)

    NG 1.2

    (1.1-1.3)

    EE = ethinyl estradiol, NG = norgestrel
  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.

    In a 107-week carcinogenicity study in mice given 10, 60, 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.

    Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

    In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6‑month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.

    13.2 Animal Toxicology and/or Pharmacology

    Embryo-fetal Development

    Rosuvastatin crosses the placenta and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.

    In female rats given oral gavage doses of 5, 15, 50 mg/kg/day rosuvastatin before mating and continuing through day 7 postcoitus results in decreased fetal body weight (female pups) and delayed ossification at the high dose (systemic exposures 10 times the human exposure at 40 mg/day based on AUC).

    In pregnant rats given oral gavage doses of 2, 10, 50 mg/kg/day from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred in groups given 50 mg/kg/day, systemic exposures ≥ 12 times the human exposure at 40 mg/day based on body surface area.

    In pregnant rabbits given oral gavage doses of 0.3, 1, 3 mg/kg/day from gestation day 6 to lactation day 18 (weaning), exposures equivalent to the human exposure at 40 mg/day based on body surface area, decreased fetal viability and maternal mortality was observed.

    Rosuvastatin was not teratogenic in rats at ≤ 25 mg/kg/day or in rabbits ≤ 3 mg/kg/day (systemic exposures equivalent to the human exposure at 40 mg/day based on AUC or body surface area, respectively).

    Central Nervous System Toxicity

    CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year.

  • 14 CLINICAL STUDIES

    14.1 Hyperlipidemia and Mixed Dyslipidemia

    CRESTOR reduces Total‑C, LDL‑C, ApoB, nonHDL‑C, and TG, and increases HDL‑C, in adult patients with hyperlipidemia and mixed dyslipidemia.

    Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with hyperlipidemia CRESTOR given as a single daily dose for 6 weeks significantly reduced Total‑C, LDL‑C, nonHDL‑C, and ApoB, across the dose range (Table 6).

    •   Table . Dose-Response in Patients With Hyperlipidemia (Adjusted Mean % Change From Baseline at Week 6)
    DoseNTotal‑CLDL‑CNon-HDL‑CApoBTGHDL‑C

    Placebo

    13

    -5

    -7

    -7

    -3

    -3

    3

    CRESTOR

    5 mg

    17

    -33

    -45

    -44

    -38

    -35

    13

    CRESTOR 10 mg

    17

    -36

    -52

    -48

    -42

    -10

    14

    CRESTOR 20 mg

    17

    -40

    -55

    -51

    -46

    -23

    8

    CRESTOR 40 mg

    18

    -46

    -63

    -60

    -54

    -28

    10

    Active-Controlled Study: CRESTOR was compared with the HMG‑CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin in a multicenter, open-label, dose-ranging study of 2240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either CRESTOR, atorvastatin, simvastatin, or pravastatin (Figure 1 and Table 7).

    •   Figure . Percent LDL‑ C Change by Dose of CRESTOR, Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Patients with Hyperlipidemia or Mixed Dyslipidemia
    figure one

    Box plots are a representation of the 25th, 50th, and 75th percentile values, with whiskers representing the 10th and 90th percentile values. Mean baseline LDL‑C: 189 mg/dL

    Table . Percent Change in LDL‑C From Baseline to Week 6 (LS Mean1) by Treatment Group (sample sizes ranging from 156–167 patients per group)

  • * CRESTOR 10 mg reduced LDL-C significantly more than atorvastatin 10 mg; pravastatin 10 mg, 20 mg, and 40 mg; simvastatin 10 mg, 20 mg, and 40 mg. (p< 0.002)
  • † CRESTOR 20 mg reduced LDL-C significantly more than atorvastatin 20 mg and 40 mg; pravastatin 20 mg and 40 mg; simvastatin 20 mg, 40 mg, and 80 mg. (p< 0.002)
  • ‡ CRESTOR 40 mg reduced LDL‑C significantly more than atorvastatin 40 mg; pravastatin 40 mg; simvastatin 40 mg, and 80 mg. (p< 0.002)
    		•

    Treatment Daily Dose

    Treatment

    10 mg

    20 mg

    40 mg

    80 mg

    CRESTOR

    -46*

    -52†

    -55‡

    ---

    Atorvastatin

    -37

    -43

    -48

    -51

    Simvastatin

    -28

    -35

    -39

    -46

    Pravastatin

    -20

    -24

    -30

    ---
  • 1 Corresponding standard errors are approximately 1.00

    • 14.2 Heterozygous Familial Hypercholesterolemia

    Active-Controlled Study: In a study of patients with heterozygous FH (baseline mean LDL of 291), patients were randomized to CRESTOR 20 mg or atorvastatin 20 mg. The dose was increased by 6-week intervals. Significant LDL-C reductions from baseline were seen at each dose in both treatment groups (Table 8).

    Table . Mean LDL-C Percentage Change from Baseline

    CRESTOR (n=435)
    LS Mean* (95% CI)    		Atorvastatin (n=187)
    LS Mean* (95% CI)
  • * LS Means are least square means adjusted for baseline LDL-C
    		•

    Week 6

    20 mg

    -47% (-49%, -46%)

    -38% (-40%, -36%)

    Week 12

    40 mg

    -55% (-57%, -54%)

    -47% (-49%, -45%)

    Week 18

    80 mg

    NA

    -52% (-54%, -50%)

    14.3 Hypertriglyceridemia

    Dose-Response Study: In a double-blind, placebo-controlled dose-response study in patients with baseline TG levels from 273 to 817 mg/dL, CRESTOR given as a single daily dose (5 to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 9).

    •   Table . Dose-Response in Patients With Primary Hypertriglyceridemia Over 6 Weeks Dosing Median (Min, Max) Percent Change From Baseline
    DosePlacebo
    (n=26)    		CRESTOR
    5 mg
    (n=25)    		CRESTOR
    10 mg
    (n=23)    		CRESTOR
    20 mg
    (n=27)    		CRESTOR
    40 mg
    (n=25)

    Triglycerides

    1 (-40, 72)

    -21 (-58, 38)

    -37 (-65, 5)

    -37 (-72, 11)

    -43 (-80, -7)

    nonHDL-C

    2 (-13, 19)

    -29 (-43, -8)

    -49 (-59, -20)

    -43 (-74, 12)

    -51 (-62, -6)

    VLDL-C

    2 (-36, 53)

    -25 (-62, 49)

    -48 (-72, 14)

    -49 (-83, 20)

    -56 (-83, 10)

    Total-C

    1 (-13, 17)

    -24 (-40, -4)

    -40 (-51, -14)

    -34 (-61, -11)

    -40 (-51, -4)

    LDL-C

    5 (-30, 52)

    -28 (-71, 2)

    -45 (-59, 7)

    -31 (-66, 34)

    -43 (-61, -3)

    HDL-C

    -3 (-25, 18)

     3 (-38, 33)

    8 (-8, 24)

    22 (-5, 50)

    17 (-14, 63)

    14.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

    In a randomized, multicenter, double-blind crossover study, 32 patients (27 with є2/є2 and 4 with apo E mutation [Arg145Cys] with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) entered a 6-week dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet. Following dietary lead-in, patients were randomized to a sequence of treatments in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg. CRESTOR reduced non HDL‑C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table below.

    Table 10. Lipid-modifying Effects of Rosuvastatin 10 mg and 20 mg in Primary Dysbetalipoproteinemia (Type III hyperlipoproteinemia) after Six weeks by Median Percent Change (95% CI) from Baseline (N=32)
    Median at Baseline (mg/dL)Median percent change from baseline (95% CI) CRESTOR 10 mgMedian percent change from baseline (95% CI) CRESTOR 20 mg

    Total-C

    342.5

    – 43.3

    (-46.9, – 37.5)

    -47.6

    (-51.6,-42.8)

    Triglycerides

    503.5

    -40.1

    (-44.9, -33.6)

    -43.0

    (-52.5, -33.1)

    NonHDL-C

    294.5

    -48.2

    (-56.7, -45.6)

    -56.4

    (-61.4, -48.5)

    VLDL-C + IDL-C

    209.5

    -46.8

    (-53.7, -39.4)

    -56.2

    (-67.7, -43.7)

    LDL-C

    112.5

    -54.4

    (-59.1, -47.3)

    -57.3

    (-59.4, -52.1)

    HDL-C

    35.5

    10.2

    (1.9, 12.3)

    11.2

    (8.3, 20.5)

    RLP-C

    82.0

    -56.4

    (-67.1, -49.0)

    -64.9

    (-74.0, -56.6)

    Apo-E

    16.0

    -42.9

    (-46.3, -33.3)

    -42.5

    (-47.1, -35.6)

    14.5 Homozygous Familial Hypercholesterolemia

    Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8‑63 years) were evaluated for their response to CRESTOR 20 to 40 mg titrated at a 6‑week interval. In the overall population, the mean LDL‑C reduction from baseline was 22%. About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL‑C, the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL‑C reduction of <15%, 3 had no change or an increase in LDL‑C. Reductions in LDL‑C of 15% or greater were observed in 3 of 5 patients with known receptor negative status.

    14.6 Pediatric Patients with Heterozygous Familial Hypercholesterolemia

    In a double blind, randomized, multicenter, placebo-controlled, 12 week study, 176 (97 male and 79 female) children and adolescents with heterozygous familial hypercholesterolemia were randomized to rosuvastatin 5, 10 or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively. Females were at least 1 year postmenarche. Mean LDL C at baseline was 233 mg/dL (range of 129 to 399). The 12 week double blind phase was followed by a 40 week open label dose-titration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg rosuvastatin daily.

    Rosuvastatin significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels at each dose compared to placebo. Results are shown in Table 11 below.

    Table 11. Lipid-modifying effects of rosuvastatin in pediatric patients 10 to 17 years of age with heterozygous familial hypercholesterolemia (least-squares mean percent change from baseline to week 12)
    Dose (mg)NLDL-CHDL-CTotal-CTG*ApoB
  • * Median percent change
  • † Difference from placebo not statistically significant
    		•

    Placebo

    46

    -1%

    +7%

    0%

    -7%

    -2%

    5

    42

    -38%

    +4%†

    -30%

    -13%†

    -32%

    10

    44

    -45%

    +11% †

    -34%

    -15%†

    -38%

    20

    44

    -50%

    +9%†

    -39%

    16%†

    -41%

    At the end of the 12 week, double blind treatment period, the percentage of patients achieving the LDL C goal of less than 110 mg/dL (2.8 mmol/L) was 0% for placebo, 12% for rosuvastatin 5 mg, 41% for rosuvastatin 10 mg and 41% for rosuvastatin 20 mg. For the 40 week, open label phase, 71% of the patients were titrated to the maximum dose of 20 mg and 41% of the patients achieved the LDL C goal of 110 mg/dL.

    The long-term efficacy of rosuvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

    14.7 Slowing of the Progression of Atherosclerosis

    In the Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin 40 mg (METEOR) study, the effect of therapy with CRESTOR on carotid atherosclerosis was assessed by B-mode ultrasonography in patients with elevated LDL‑C, at low risk (Framingham risk <10% over ten years) for symptomatic coronary artery disease and with subclinical atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind, placebo-controlled clinical study 984 patients were randomized (of whom 876 were analyzed) in a 5:2 ratio to CRESTOR 40 mg or placebo once daily. Ultrasonograms of the carotid walls were used to determine the annualized rate of change per patient from baseline to two years in mean maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the maximum cIMT analyzed over all 12 carotid artery sites between patients treated with CRESTOR and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, –0.0093; p< 0.0001).

    The annualized rate of change from baseline for the placebo group was +0.0131 mm/year (p< 0.0001). The annualized rate of change from baseline for the group treated with CRESTOR was -0.0014 mm/year (p=0.32).

    At an individual patient level in the group treated with CRESTOR, 52.1% of patients demonstrated an absence of disease progression (defined as a negative annualized rate of change), compared to 37.7% of patients in the placebo group.

    14.8 Primary Prevention of Cardiovascular Disease

    In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of CRESTOR (rosuvastatin calcium) on the occurrence of major cardiovascular (CV) disease events was assessed in 17,802 men (≥50 years) and women (≥60 years) who had no clinically evident cardiovascular disease, LDL‑C levels <130 mg/dL (3.3 mmol/l) and hs‑CRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL‑C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%). Study participants had a median baseline LDL‑C of 108 mg/dL and hsCRP of 4.3 mg/L. Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects.

    The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure.

    Rosuvastatin significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p< 0.001) relative risk reduction of 44% and absolute risk reduction of 1.2% (see Figure 2). The risk reduction for the primary end point was consistent across the following predefined subgroups: age, sex, race, smoking status, family history of premature CHD, body mass index, LDL‑C, HDL‑C, and hsCRP levels.

    Figure . Time to first occurrence of major cardiovascular events in JUPITER

    figure two

    The individual components of the primary end point are presented in Figure 3. Rosuvastatin significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the rosuvastatin and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina.

    Rosuvastatin significantly reduced the risk of myocardial infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in rosuvastatin-treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in rosuvastatin-treated subjects).

    In a post-hoc subgroup analysis of JUPITER subjects (n=1405; rosuvastatin=725, placebo=680) with a hsCRP ≥2 mg/L and no other traditional risk factors (smoking, BP ≥140/90 or taking antihypertensives, low HDL‑C) other than age, after adjustment for high HDL‑C, there was no significant treatment benefit with rosuvastatin treatment.

    Figure . Major CV events by treatment group in JUPITER

    figure three

    At one year, rosuvastatin increased HDL‑C and reduced LDL‑C, hsCRP, total cholesterol and serum triglyceride levels (p< 0.001 for all versus placebo).

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    CRESTOR® (rosuvastatin calcium) Tablets are supplied as:

    • 10 mg. Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side; overbagged with 10 tablets per bag, NC 55154-6921-0

    Storage

    Store at controlled room temperature, 20‑25ºC (68-77ºF) [see USP Controlled Room Temperature]. Protect from moisture.

  • 17 PATIENT COUNSELING INFORMATION

    Patients should be instructed not to take 2 doses of CRESTOR within 12 hours of each other.

    17.1 Skeletal Muscle Effects

    Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing CRESTOR.

    17.2 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.

    17.3 Pregnancy

    If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.

    17.4 Liver Enzymes
    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.
    CRESTOR is a trademark of the AstraZeneca group of companies.
    © AstraZeneca 2015
    Licensed from SHIONOGI & CO., LTD., Osaka, Japan
    Distributed by:
    AstraZeneca Pharmaceuticals LP
    Wilmington, DE 19850
    ASTRAZENECA
    Distributed by:
    Cardinal Health
    Dublin, OH 43017

    Rev. June, 2015

  • PATIENT INFORMATION

    CRESTOR® (Kres-tor)

    rosuvastatin calcium

    Tablets

    Read this Patient Information carefully before you start taking CRESTOR and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

    If you have any questions about CRESTOR, ask your doctor. Only your doctor can determine if CRESTOR is right for you.

    What is CRESTOR?

    CRESTOR is a prescription medicine that contains a cholesterol-lowering medicine called rosuvastatin calcium. CRESTOR is used along with diet to:

    • lower the level of your “bad” cholesterol (LDL)
    • increase the level of your “good” cholesterol (HDL)
    • lower the level of fat in your blood (triglycerides)
    • slow the buildup of fatty deposits (plaque) in the walls of blood vessels

    CRESTOR is for patients who cannot control their cholesterol levels by diet and exercise alone. CRESTOR is used to reduce the risk of heart attacks and strokes in men 50 years of age and older and women 60 years of age and older who do not have known heart disease but do have certain additional risk factors.

    It is not known if CRESTOR is safe and effective in people who have Fredrickson Type I and V dyslipidemias. It is not known if CRESTOR is safe and effective in children under 10 years of age or in girls who have not started their period (menses).

    Who should not take CRESTOR?

    Do not take CRESTOR if you:

    • are allergic to rosuvastatin calcium or any of the ingredients in CRESTOR. See the end of this leaflet for a complete list of ingredients in CRESTOR.
    • have liver problems.
    • are pregnant or think you may be pregnant, or are planning to become pregnant. CRESTOR may harm your unborn baby. If you become pregnant, stop taking CRESTOR and call your doctor right away.
    • are breastfeeding. Medicines like CRESTOR can pass into your breast milk and may harm your baby. It is not known if CRESTOR passes into your breast milk. You and your doctor should decide the best way to feed your baby if you take CRESTOR.

    What should I tell my doctor before and while taking CRESTOR?

    Tell your doctor if you:

    • have unexplained muscle aches or weakness
    • have or have had kidney problems
    • have or have had liver problems
    • drink more than 2 glasses of alcohol daily
    • have thyroid problems
    • are 65 years of age or older
    • are of Asian descent
    • are pregnant or think you may be pregnant, or are planning to become pregnant
    • are breastfeeding

    Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    Talk to your doctor before you start taking any new medicines.

    Taking CRESTOR with certain other medicines may affect each other causing side effects. CRESTOR may affect the way other medicines work, and other medicines may affect how CRESTOR works.

    Especially tell your doctor if you take:

    • cyclosporine (a medicine for your immune system)
    • gemfibrozil (a fibric acid medicine for lowering cholesterol)
    • anti-viral medicines including HIV or hepatitis C protease inhibitors (such as lopinavir, ritonavir, fosamprenavir, tipranavir, atazanavir, or simeprevir)
    • certain anti-fungal medicines (such as itraconazole, ketoconazole and fluconazole
    • coumarin anticoagulants (medicines that prevent blood clots, such as warfarin)
    • niacin or nicotinic acid
    • fibric acid derivatives (such as fenofibrate)
    • colchicine (a medicine used to treat gout)

    Ask your doctor or pharmacist for a list of these medicines if you are not sure.

    Know all of the medicines you take. Keep a list of them to show your doctor and pharmacist when you get new medicine.

    How should I take CRESTOR?

    • Take CRESTOR exactly as your doctor tells you to take it.
    • Take CRESTOR, by mouth, 1 time each day. Swallow the tablet whole.
    • CRESTOR can be taken at any time of day, with or without food.
    • Do not change your dose or stop CRESTOR without talking to your doctor, even if you are feeling well.
    • Your doctor may do blood tests to check your cholesterol levels before and during your treatment with CRESTOR. Your doctor may change your dose of CRESTOR if needed.
    • Your doctor may start you on a cholesterol lowering diet before giving you CRESTOR. Stay on this diet when you take CRESTOR. Wait at least 2 hours after taking CRESTOR to take an antacid that contains a combination of aluminum and magnesium hydroxide.
    • If you miss a dose of CRESTOR, take it as soon as you remember.
    • However, do not take 2 doses of CRESTOR within 12 hours of each other.
    • If you take too much CRESTOR or overdose, call your doctor or go to the nearest hospital emergency room right away.

    What are the Possible Side Effects of CRESTOR?

    CRESTOR may cause serious side effects, including:

    • Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death. Tell your doctor right away if:
      • you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take CRESTOR.
      • you have muscle problems that do not go away even after your doctor has told you to stop taking CRESTOR. Your doctor may do further tests to diagnose the cause of your muscle problems.
    •   Your chances of getting muscle problems are higher if you:
      • are taking certain other medicines while you take CRESTOR
      • are 65 years of age or older
      • have thyroid problems (hypothyroidism) that are not controlled
      • have kidney problems
      • are taking higher doses of CRESTOR
    • Liver problems. Your doctor should do blood tests to check your liver before you start taking CRESTOR and if you have symptoms of liver problems while you take CRESTOR. Call your doctor right away if you have any of the following symptoms of liver problems:
      • feel unusually tired or weak
      • loss of appetite
      • upper belly pain
      • dark urine
      • yellowing of your skin or the whites of your eyes

    The most common side effects may include: headache, muscle aches and pains, abdominal pain, weakness, and nausea.

    Additional side effects that have been reported with CRESTOR include

    memory loss and confusion.

    Tell your doctor if you have any side effect that bothers you or that does not go away.

    These are not all the possible side effects of CRESTOR. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store CRESTOR?

    • Store CRESTOR at room temperature, between 68°F to 77°F (20°C to 25°C) and in a dry place.
    • Safely throw away medicine that is out of date or no longer needed.

    Keep CRESTOR and all medicines out of the reach of children.

    What are the Ingredients in CRESTOR?

    Active Ingredient: rosuvastatin as rosuvastatin calcium

    Inactive Ingredients: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide NF.

    General Information about the safe and effective use of CRESTOR

    Most of the cholesterol in your blood is made in the liver. CRESTOR works by reducing cholesterol in two ways: CRESTOR blocks an enzyme in the liver causing the liver to make less cholesterol, and CRESTOR increases the uptake and breakdown by the liver of cholesterol already in the blood.

    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CRESTOR for a condition for which it was not prescribed. Do not give CRESTOR to other people, even if they have the same medical condition you have. It may harm them.

    This Patient Information summarizes the most important information about CRESTOR. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about CRESTOR that is written for health professionals.

    For more information, go to the CRESTOR website at www.crestor.com or call 1-800-CRESTOR.

    CRESTOR is a trademark of the AstraZeneca group of companies.

    © AstraZeneca 2015

    Licensed from SHIONOGI & CO., LTD., Osaka, Japan

    Distributed by:

    AstraZeneca Pharmaceuticals LP

    Wilmington, DE 19850

    Distributed by:
    Cardinal Health

    Dublin, OH 43017

    Revised June, 2015

    ASTRAZENECA

    L37412460318

  • Package/Label Display Panel

    Crestor 10 mg Tablets

    Rosuvastatin Calcium

    10 Tablets

    bag label
  • INGREDIENTS AND APPEARANCE
    CRESTOR 
    rosuvastatin calcium tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 55154-6921(NDC:0310-0751)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ROSUVASTATIN CALCIUM (UNII: 83MVU38M7Q) (ROSUVASTATIN - UNII:413KH5ZJ73) ROSUVASTATIN10 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    TRIBASIC CALCIUM PHOSPHATE (UNII: 91D9GV0Z28)  
    CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    TRIACETIN (UNII: XHX3C3X673)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    Product Characteristics
    ColorPINKScoreno score
    ShapeROUND (biconvex) Size7mm
    FlavorImprint Code 10;crestor
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 55154-6921-010 in 1 BAG12/01/2010
    11 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02136612/01/2010
    Labeler - Cardinal Health (603638201)

    • Trademark Results [CRESTOR]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    CRESTOR
    CRESTOR
    75878423 2532819 Live/Registered
    IPR PHARMACEUTICALS INC.
    1999-12-21
    CRESTOR
    CRESTOR
    75819391 not registered Dead/Abandoned
    Crest Microsystems Inc.
    1999-10-12
    CRESTOR
    CRESTOR
    75445606 2245933 Live/Registered
    CRESTOR, INC.
    1998-03-05
    CRESTOR
    CRESTOR
    74642072 not registered Dead/Abandoned
    Crest Microsystem Inc.
    1995-03-06
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