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Crestor

2015-02-09 20:52:53 来源: 作者: 【大中小】浏览:340次评论:0条

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FULL PRESCRIBING INFORMATION

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.

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

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

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.

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.

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.

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)].

The recommended starting dose of CRESTOR is 10 mg once daily. For patients with marked hyperlipidemia (LDL-C greater than 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.

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

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)].

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)].

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)].

For patients with severe renal impairment (CL less than 30 mL/min/1.73 m) 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)].

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.

CRESTOR is contraindicated in the following conditions:

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.

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)]

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)]

In the CRESTOR clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among CRESTOR treated patients. These findings were more frequent in patients taking CRESTOR 40 mg, when compared to lower doses of CRESTOR or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on CRESTOR therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

Although clinical studies have shown that CRESTOR alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if CRESTOR is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

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 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:

The most commonly reported adverse reactions (incidence ≥ 2%) in the CRESTOR controlled clinical trial database of 5,394 patients were:

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.

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.

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.

Table 1. Adverse Reactions* Reported by ≥ 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

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
Myalgia	12.7	12.1
Arthralgia	10.0	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

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)].

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)].

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)]

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)]

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)]

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)].

CRESTOR is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy. [see Contraindications (4)]

There are no adequate and well-controlled studies of CRESTOR in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.

Rosuvastatin crosses the placenta in rats and rabbits. In rats, CRESTOR was not teratogenic at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10-12 times the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight among female pups, and delayed ossification. In rabbits, pup viability decreased and maternal mortality increased at doses equivalent to the human dose of 40 mg/day. [see Nonclinical Toxicology (13.2)]

CRESTOR may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking CRESTOR, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.

It is not known whether rosuvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of rosuvastatin are three times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require CRESTOR treatment should be advised not to nurse their infants. [see Contraindications (4)]

The safety and effectiveness of CRESTOR in pediatric patients have not been established.

Treatment experience with CRESTOR in a pediatric population is limited to 8 patients with homozygous FH. None of these patients was below 8 years of age.

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

Of the 10,275 patients in clinical studies with CRESTOR, 3,159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients are at higher risk of myopathy and CRESTOR should be prescribed with caution in the elderly. [see Warnings and Precautions, (5.1) and Clinical Pharmacology, (12.3)]

Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CL greater than or equal to 30 mL/min/1.73 m); 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 (CL less than 30 mL/min/1.73 m) not requiring hemodialysis. [see Dosage and Administration (2.7) and Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

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)].

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)]

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.

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

The empirical formula for rosuvastatin calcium is (CHFNOS)Ca 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.

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.

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.

Drug-Drug Interactions:

Cytochrome P450 3A4

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

EE = ethinyl estradiol, NG = norgestrel

* Clinically significant pharmacodynamic effects [See Warnings and Precautions (5.4)]

Table 3. Effect of Co-administered Drugs on Rosuvastatin Systemic Exposure
Co-administered drug and dosing regimen		Rosuvastatin
	Dose (mg) *	Change in AUC	Change in C_max
Cyclosporine – stable dose required (75 mg – 200 mg BID)	10 mg QD for 10 days	↑ 7-fold†	↑ 11-fold†
Gemfibrozil 600 mg BID for 7 days	80 mg	↑ 1.9-fold†	↑ 2.2-fold†
Lopinavir/ritonavir combination 400 mg/100 mg BID for 10 days	20 mg QD for 7 days	↑ 2-fold†	↑ 5-fold†
Fenofibrate 67 mg TID for 7 days	10 mg	↑ 7%	↑ 21%
Aluminum & magnesium hydroxide combination antacid Administered simultaneously Administered 2 hours apart	40 mg 40 mg	↓ 54%† ↓ 22%	↓ 50%† ↓ 16%
Erythromycin 500 mg QID for 7 days	80 mg	↓ 20%	↓ 31%
Ketoconazole 200 mg BID for 7 days	80 mg	↑ 2%	↓ 5%
Itraconazole 200 mg QD for 5 days	10 mg 80 mg	↑ 39% ↑ 28%	↑ 36% ↑ 15%
Fluconazole 200 mg QD for 11 days	80 mg	↑ 14%	↑ 9%

Table 4. Effect of Rosuvastatin Co-Administration on Systemic Exposure To Other Drugs
Rosuvastatin		Co-administered Drug
Dosage Regimen
	Name and Dose	Change in AUC	Change in C_max
40 mg QD for 10 days	Warfarin *25 mg single dose	R-Warfarin ↑ 4% S-Warfarin ↑ 6%	R-Warfarin ↓ 1% S-Warfarin 0%
40 mg QD for 12 days	Digoxin 0.5 mg single dose	↑ 4%	↑ 4%
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 ↑ 26% NG ↑ 34%	EE ↑ 25% NG ↑ 23%

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.

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.

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 5).

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 2,240 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 6).

Figure 1. Percent LDL-C Change by Dose of CRESTOR,

Atorvastatin, Simvastatin, and Pravastatin

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

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 8).

In a randomized, multi-center, 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 nonHDL-C (primary endpoint) and circulating remnant lipoprotein levels. Results are shown in the table below.

Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8-63 years) were eva luated 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 less than 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.

In the Measuring Effects on Intima Media Thickness: an eva luation 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 less than 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 CRESTOR-treated patients and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, –0.0093; p less than 0.0001).

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

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.

Table 5. Dose-Response in Patients With Hyperlipidemia (Adjusted Mean % Change From Baseline at Week 6)
Dose	N	Total-C	LDL-C	Non-HDL-C	ApoB	TG	HDL-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

Table 7. Mean LDL-C Percentage Change from Baseline
		CRESTOR (n=435) * LS Mean (95% CI)	Atorvastatin (n=187) LS (Mean 95% CI)
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%)

Table 8. Dose-Response in Patients With Primary Hypertriglyceridemia Over 6 Weeks Dosing Median (Min, Max) Percent Change From Baseline
Dose	Placebo (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)