降血脂藥物
Dyslipidemia

Adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

Adjunctive therapy to other lipid-lowering treatments (eg, LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, total-C and Apo B in adult patients with homozygous familial hypercholesterolemia.

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, III and V dyslipidemias.

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.

Hyperlipidemia, Mixed Dyslipidemia and Hypertriglyceridemia: Dose Range: 5-20 mg once daily. Therapy with Crestor should be individualized according to goal of therapy and response. Usual Recommended Starting Dose: 10 mg once daily. However, initiation of therapy with 5 mg once daily should be considered for patients requiring less aggressive LDL-C reductions, who have predisposing factors for myopathy and as noted as follows for special populations eg, patients taking cyclosporine, Asian patients and patients with severe renal insufficiency (see Pharmacokinetics and Drug-Drug Interactions under Pharmacology). For patients with marked hypercholesterolemia (LDL-C >190 mg/dL) and aggressive lipid targets, a 20-mg starting dose may be considered. After initiation and/or upon titration of Crestor, lipid levels should be analyzed within 2-4 weeks and dosage adjusted accordingly.

When initiating statin therapy or switching from another statin therapy, the appropriate Crestor starting dose should first be utilized and only then titrated according to the patient's individualized goal of therapy.

Homozygous Familial Hypercholesterolemia: Recommended Starting Dose: 20 mg once daily. Response to therapy should be estimated from pre-apheresis LDL-C levels.

Asian Patients: Initiation of Crestor therapy with 5 mg once daily should be considered for Asian patients (see Asian Patients under Precautions and Pharmacology under Actions).

Use with Cyclosporine or Lopinavir/Ritonavir: In patients taking cyclosporine, dose of Crestor should be limited to 5 mg once daily (see Precautions and Interactions). In patients taking a combination of lopinavir and ritonavir, the dose of Crestor should be limited to 10 mg once daily (see Precautions and Interactions).

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 Precautions and Interactions).

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 Precautions and Interactions ).

Patients with Severe Renal Impairment: For patients with severe renal impairment (creatinine clearance <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 Precautions and Pharmacology under Actions).

Active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels (see Precautions).

Use in pregnancy & lactation: Teratogenic Effects: Pregnancy Category X: Crestor is contraindicated in women who are pregnant 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.

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 3- to 4-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the 1st 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 under Actions.)

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 Crestor, 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 Toxicology under Actions).

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 3 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 the potential to cause serious adverse reactions in nursing infants, women who require Crestor treatment should be advised not to breastfeed their infants.

Crestor should be prescribed with caution in patients with predisposing factors for myopathy (eg, ≥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 or lopinavir/ritonavir. (See Dosage & Administration and Interactions.)

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 (eg, sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

Liver Enzyme Abnormalities and Monitoring: It is recommended that liver enzyme tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose and periodically (eg, 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 2 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 Pharmacology under Actions). Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of Crestor. (See Contraindications.)

Concomitant Coumarin Anticoagulants: Caution should be exercised when anticoagulants are given in conjunction with Crestor because of the potentiation 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 (see Interactions).

Proteinuria and Hematuria: In the Crestor clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among Crestor-treated patients. This finding was 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.

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 eg, ketoconazole, spironolactone and cimetidine.

Renal Impairment: Rosuvastatin exposure is not influenced by mild to moderate renal impairment (creatinine clearance ≥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 (creatinine clearance <30 mL/min/1.73 m²) not requiring hemodialysis (see Dosage & Administration and Pharmacology under Actions).

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 and Pharmacology under Actions).

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 & Administration and Pharmacology under Actions).

Use in children: 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 <8 years.

In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10-17 years with heterozygous FH received single and multiple oral doses of Crestor. Both C_max and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses.

Use in the elderly: Of the 10,275 patients in clinical studies with Crestor, 3159 (31%) were ≥65 years and 698 (6.8%) were ≥75 years. 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 Pharmacology under Actions).

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 Precautions); elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase and bilirubin; and thyroid function abnormalities.

Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of Crestor: Arthralgia, 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.
View ADR Monitoring Website[參閱藥物不良反應監測表格]

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 & Administration and Pharmacology under Actions).

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 & Administration, Precautions and Pharmacology under Actions).

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 Precautions and Pharmacology under Actions).

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 Precautions).

Fenofibrate: When Crestor was co-administered 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 Precautions and Pharmacology under Actions).
View more drug interactions with Crestor[冠脂妥]

Rosuvastatin calcium is a synthetic lipid-lowering agent for oral administration. It 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. Its empirical formula 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. It is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.

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 (see figure and Table 2).

Hypertriglyceridemia: Dose-Response Study: In a double-blind, placebo-controlled, dose-response study in patients with baseline TG levels from 273-817 mg/dL, Crestor given as a single daily dose (5-40 mg) over 6 weeks significantly reduced serum TG levels (see Table 4).

Results of the METEOR Study: 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 10 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 2 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 Crestor-treated patients and placebo-treated patients was -0.0145 mm/year (95% CI -0.0196, -0.0093; p<0.0001).

At an individual patient level in the Crestor group, 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.

Administration of Crestor with food did not affect the AUC of rosuvastatin.

Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 L. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination t_½ of rosuvastatin is approximately 19 hrs.

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 1 conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and C_max) in Asian subjects when compared with a Caucasian control group.

Geriatric: There were no differences in plasma concentrations of rosuvastatin between the non-elderly and elderly populations (≥65 years).

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.

In patients with Child-Pugh A disease, C_max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C_max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

Toxicology: Nonclinical Toxicology: Carcinogenicity, Mutagenicity, 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.

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.

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 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.

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).