These highlights do not include all the information needed to use CRESTOR safely and effectively. See full prescribing information for CRESTOR.
Initial U.S. Approval: 2003
RECENT MAJOR CHANGES
Indications and Usage, Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) (1.3) 10/2008
INDICATIONS AND USAGE
CRESTOR is an HMG Co-A reductase inhibitor indicated for:
patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDL-C (1.1)
patients with hypertriglyceridemia as an adjunct to diet (1.2)
patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia) as an adjunct to diet (1.3)
patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total-C, and ApoB (1.4)
slowing the progression of atherosclerosis as part of a treatment strategy to lower total-C and LDL-C as an adjunct to diet (1.5)
Limitations of use (1.6):
Effect of CRESTOR on cardiovascular morbidity and mortality has not been determined.
CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias.
DOSAGE AND ADMINISTRATION
CRESTOR can be taken with or without food, at any time of day. (2.1)
Dose range: 5-40 mg once daily. Use 40 mg dose only for patients not reaching LDL-C goal with 20 mg. (2.1)
Hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia, primary dysbetalipoproteinemia, and atherosclerosis: Starting dose 10 mg. Consider 20 mg starting dose for patients with LDL-C>190 mg/dL and aggressive lipid targets. (2.2)
HoFH: Starting dose 20 mg. (2.3)
DOSAGE FORMS AND STRENGTHS
Tablets: 5 mg, 10 mg, 20 mg, and 40 mg (3)
CONTRAINDICATIONS
Known hypersensitivity to product components (4)
Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4)
Women who are pregnant or may become pregnant (4, 8.1)
Nursing mothers (4, 8.3)
WARNINGS AND PRECAUTIONS
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with use of 40 mg dose, advanced age (>65), hypothyroidism, renal impairment, and combination use with cyclosporine, lopinavir/ritonavir, or certain other lipid-lowering drugs. Advise patients to promptly report unexplained muscle pain, tenderness, or weakness and discontinue CRESTOR if signs or symptoms appear (5.1)
Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminases can occur. Monitor liver enzymes before and during treatment. (5.2)
ADVERSE REACTIONS
Most frequent adverse reactions (rate > 2%) are headache, myalgia, abdominal pain, asthenia, and nausea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
Cyclosporine: Combination increases rosuvastatin exposure. Limit CRESTOR dose to 5 mg once daily. (2.5, 7.1)
Gemfibrozil: Combination should be avoided. If used together, limit CRESTOR dose to 10 mg once daily. (2.6, 5.1, 7.2)
Lopinavir/Ritonavir: Combination increases rosuvastatin exposure. Limit CRESTOR dose to 10 mg once daily. (2.5, 5.1, 7.3)
Coumarin anti-coagulants: Combination prolongs INR. Achieve stable INR prior to starting CRESTOR. Monitor INR frequently until stable upon initiation or alteration of CRESTOR therapy. (5.3, 7.4)
Concomitant lipid-lowering therapies: Use with fibrates and niacin products may increase the risk of skeletal muscle effects. (2.6, 5.1, 7.5, 7.6)
USE IN SPECIFIC POPULATIONS
Pediatric use: Safety and effectiveness not established. (8.4)
Severe renal impairment (not on hemodialysis): Starting dose is 5 mg, not to exceed 10 mg. (2.7, 5.1, 8.6)
Asian population: Consider 5 mg starting dose. (2.4, 8.8)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 09/2009
Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
*Sections or subsections omitted from the full prescribing information are not listed
Recent Major Changes
1INDICATIONS AND USAGE
1.1 Hyperlipidemia and Mixed Dyslipidemia
1.2 Hypertriglyceridemia
1.3 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
1.4 Homozygous Familial Hypercholesterolemia
1.5 Slowing of the Progression of Atherosclerosis
1.6 Limitations of Use
2DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
2.2 Hyperlipidemia, Mixed Dyslipidemia, Hypertriglyceridemia, Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia), and Slowing of the Progression of Atherosclerosis
2.3 Homozygous Familial Hypercholesterolemia
2.4 Dosage in Asian Patients
2.5 Use with Cyclosporine, or Lopinavir/Ritonavir
2.6 Concomitant Lipid-Lowering Therapy
2.7 Dosage in Patients With Severe Renal Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Skeletal Muscle Effects
5.2 Liver Enzyme Abnormalities and Monitoring
5.3 Concomitant Coumarin Anticoagulants
5.4 Proteinuria and Hematuria
5.5 Endocrine Effects
6ADVERSE REACTIONS
6.1 Clinical Studies Experience
6.2Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Cyclosporine
7.2 Gemfibrozil
7.3 Lopinavir/Ritonavir
7.4 Coumarin Anticoagulants
7.5 Niacin
7.6 Fenofibrate
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.3Nursing Mothers
8.4 Pediatric Use
8.5Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
8.8 Asian Patients
10OVERDOSAGE
11DESCRIPTION
12CLINICAL PHARMACOLOGY
12.1Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Hyperlipidemia and Mixed Dyslipidemia
14.2Heterozygous Familial Hypercholesterolemia
14.3 Hypertriglyceridemia
14.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
14.5 Homozygous Familial Hypercholesterolemia
14.6 Slowing of the Progression of Atherosclerosis
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Skeletal Muscle Effects
17.2 Concomitant Use of Antacids
17.3 Pregnancy
17.4 Liver Enzymes
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FULL PRESCRIBING INFORMATION
1INDICATIONS 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 non-pharmacological interventions alone has been inadequate.
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 Limitations of Use
The effect of CRESTOR on cardiovascular morbidity and mortality has not been determined.
CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias.
2DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
The dose range for CRESTOR is 5 to 40 mg orally once daily.
CRESTOR can be administered as a single dose at any time of day, with or without food.
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.
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 [see Warnings and Precautions (5.1)].
2.2 Hyperlipidemia, Mixed Dyslipidemia, Hypertriglyceridemia, Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia), and Slowing of the Progression of Atherosclerosis
The recommended starting dose of CRESTOR is 10 mg once daily. For patients with marked hyperlipidemia (LDL-C > 190 mg/dL) and aggressive lipid targets, a 20 mg starting dose may be considered.
After initiation or upon titration of CRESTOR, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly.
2.3 Homozygous Familial Hypercholesterolemia
The recommended starting dose of CRESTOR is 20 mg once daily. Response to therapy should be estimated from pre-apheresis LDL-C levels.
2.4 Dosage in Asian Patients
Initiation of CRESTOR therapy with 5 mg once daily should be considered for Asian patients. [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].
2.5 Use with Cyclosporine, or Lopinavir/Ritonavir
In patients taking cyclosporine, the dose of CRESTOR should be limited to 5 mg once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]. In patients taking a combination of lopinavir and ritonavir the dose of CRESTOR should be limited to 10 mg once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].
2.6 Concomitant Lipid-Lowering Therapy
The risk of skeletal muscle effects may be enhanced when CRESTOR is used in combination with niacin or fenofibrate; a reduction in CRESTOR dosage should be considered in this setting. [see Warnings and Precuations (5.1) and see Drug Interactions (7.5, 7.6)]
Combination therapy with gemfibrozil should be avoided because of an increase in CRESTOR exposure with concomitant use; if CRESTOR is used in combination with gemfibrozil, the dose of CRESTOR should be limited to 10 mg once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.2)].
2.7 Dosage 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 [see Use 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 [see Adverse Reactions (6.1)].
Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see Warnings 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. [see Use 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. [see Use 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, 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.
5.2 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 (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 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 (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
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.
6ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis). [see Warnings and Precautions (5.1)]
Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
In the CRESTOR controlled clinical trials database (placebo or active-controlled) of 5,394 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 5,394 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 or equal to placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.
Table 1. Adverse Reactions* Reported by ≥ 2% of Patients Treated with CRESTOR and ≥ Placebo in Placebo-Controlled Trials (% of Patients)
Adverse reactions by COSTART preferred term.
*
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 [see Warnings 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 CRESTOR-treated subjects 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 [see Clinical Studies (14.5)]
Adverse reactions reported in ≥ 2% of patients and at a rate greater than or equal to placebo are shown in Table 2.
Table 2. Adverse Reactions* Reported by ≥ 2% of Patients Treated with CRESTOR and ≥ Placebo in the METEOR Trial (% of Patients)
Adverse Reactions
CRESTOR 40 mg
Placebo
N = 700
N = 281
Adverse reactions by MedDRA preferred term.
*
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
6.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of CRESTOR: arthralgia, hepatic failure, hepatitis, jaundice and memory loss. 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.
7 DRUG INTERACTIONS
7.1 Cyclosporine
Cyclosporine significantly increased rosuvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to CRESTOR 5 mg once daily. [see Dosage and Administration (2.5), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
7.2 Gemfibrozil
Gemfibrozil significantly increased rosuvastatin exposure. Therefore, combination therapy with CRESTOR and gemfibrozil should be avoided. If used, do not exceed CRESTOR 10 mg once daily. [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].
7.3 Lopinavir/Ritonavir
The combination of lopinavir and ritonavir significantly increased rosuvastatin exposure. Therefore, in patients taking a combination of lopinavir and ritonavir, the dose of CRESTOR should be limited to 10 mg once daily. The effect of other protease inhibitors on rosuvastatin pharmacokinetics has not been examined. [see Dosage and Administration (2.5), Warnings and Precautions (5.1) and Clinical 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. [see Warnings 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 niacin; a reduction in CRESTOR dosage should be considered in this setting [see Warnings 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. The benefit of further alterations in lipid levels by the combined use of CRESTOR with fibrates should be carefully weighed against the potential risks of this combination. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy
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.
8.3Nursing 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. [see Contraindications (4)]
8.4 Pediatric Use
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.
8.5Geriatric Use
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, (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. [see Dosage and Administration (2.7) and 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. [see Contraindications (4) and Warning and Precautions (5.2) and Clinical 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. [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]
10OVERDOSAGE
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.
11DESCRIPTION
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:
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 is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3- methylglutaryl coenzyme A to meva lonate, 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 hemodialyis 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:
Cytochrome P450 3A4
Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent.
Table 3. Effect of Co-administered Drugs on Rosuvastatin Systemic Exposure
Co-administered drug and dosing regimen
Rosuvastatin
*
Single dose unless otherwise noted
Clinically significant [see Dosage and Administration (2) and Warnings and Precautions (5)
