Achieving LDL cholesterol, non-HDL cholesterol, and apolipoprotein B target levels in high-risk...

May 2006, Volume 151, Number 5

Achieving LDL cholesterol, non-HDL cholesterol, and apolipoprotein B target levels in high-risk patients: Measuring

Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) II

Christie M. Ballantyne, MD, Marcelo Bertolami, MD, Hugo Ricardo Hernandez Garcia, MD,

Daniel Nul, MD, Evan A. Stein, MD, Pierre Theroux, MD, Robert Weiss, MD, Valerie A. Cain, MS, and Joel S. Raichlen, MD

Information Provided by AstraZeneca Pharmaceuticals LP CRESTOR® (rosuvastatin calcium) is indicated as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, non-HDL-C, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. This paper includes secondary efficacy measures on hs-CRP, apolipoprotein A-1, and various lipid ratios for which CRESTOR is not indicated. CRESTOR is contraindicated in patients with a known hypersensitivity to any component of this product, in patients with active liver disease or with unexplained persistent elevations of serum transaminases, in women who are or may become pregnant, and in nursing mothers. It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (eg, semiannually) thereafter. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of CRESTOR is recommended. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with CRESTOR and with other drugs in this class. Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy with CRESTOR should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. The adverse event information found within the prescribing information for CRESTOR is based on a patient database of 10,275. CRESTOR was generally well tolerated. The most frequent adverse events thought to be related to CRESTOR were myalgia (3.3%), constipation (1.4%), asthenia (1.3%), abdominal pain (1.3%), and nausea (1.3%).* This study of 774 patients (391 of 774 patients were randomized to CRESTOR) provides a subset of the adverse event information and may not be representative of the entire patient database.

The dose range for CRESTOR is 5 mg to 40 mg once daily. Therapy with CRESTOR should be individualized according to goal of therapy and response. The usual recommended starting dose of CRESTOR is 10 mg once daily. Initiation of therapy with 5 mg once daily should be considered for patients requiring less aggressive LDL-C reductions, patients who have predisposing factors for myopathy, patients taking cyclosporine, Asian patients, and patients with severe renal insufficiency. For patients with marked hypercholesterolemia (LDL-C >190 mg/dL) and aggressive lipid targets, a 20-mg starting dose may be considered. The 40-mg dose of CRESTOR is reserved only for those patients not achieving LDL-C goal at 20 mg. Patients initiating statin therapy or switching from another statin should begin treatment with CRESTOR at the appropriate starting dose. After initiation and/or upon titration of CRESTOR, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. The effect of CRESTOR on cardiovascular morbidity and mortality has not been determined; long-term outcome studies are currently under way. Impact on clinical outcomes of the differences between treatments studied is not known. CRESTOR is a registered trademark of the AstraZeneca group of companies. *Prescribing Information; Data on file, DA-CRS-01. 237802 24/06

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Achieving LDL cholesterol, non-HDL cholesterol, andapolipoprotein B target levels in high-risk patients:Measuring Effective Reductions in Cholesterol UsingRosuvastatin therapY (MERCURY) IIChristie M. Ballantyne, MD,a Marcelo Bertolami, MD,b Hugo Ricardo Hernandez Garcia, MD,c Daniel Nul, MD,d

Evan A. Stein, MD,e Pierre Theroux, MD,f Robert Weiss, MD,g Valerie A. Cain, MS,h and Joel S. Raichlen, MDh

Houston, TX; Sao Paulo, Brazil; Guadalajara, Mexico; Buenos Aires, Argentina; Highland Heights, KY;Montreal, Quebec, Canada; Auburn, ME; and Wilmington, DE

Background National Cholesterol Education Program Adult Treatment Panel III guidelines for patients at a highrisk of coronary heart disease set a low-density lipoprotein cholesterol (LDL-C) target of b100 mg/dL. This target can bedifficult to attain with diet and current therapy.

Methods In a 16-week multinational trial, 1993 high-risk patients were randomized to rosuvastatin 20 mg,atorvastatin 10 mg, atorvastatin 20 mg, simvastatin 20 mg, or simvastatin 40 mg for 8 weeks. Patients either remainedon starting treatment or switched to lower or milligram-equivalent doses of rosuvastatin for 8 more weeks.

Results At 16 weeks, more patients achieved their LDL-C target by switching to rosuvastatin 10 mg than staying onatorvastatin 10 mg (66% vs 42%, P b .001) or simvastatin 20 mg (73% vs 32%, P b .001). Changing to rosuvastatin20 mg brought more patients to their LDL-C target than staying on atorvastatin 20 mg (79% vs 64%, P b .001) orsimvastatin 40 mg (84% vs 56%, P b .001). More very high risk patients achieved an LDL-C target of b70 mg/dL whenchanged to rosuvastatin from atorvastatin or simvastatin (within-arm comparisons P b .01). More hypertriglyceridemicpatients (triglycerides z200 mg/dL) met LDL-C, non–high-density lipoprotein cholesterol (non–HDL-C), and apolipoproteinB targets by changing to rosuvastatin. Switching to rosuvastatin produced greater reductions in LDL-C, total cholesterol,non–HDL-C, apolipoprotein B, and lipid ratios. All treatments were well tolerated, with no differences among treatmentgroups in skeletal muscle, hepatic, or renal toxicity.

Conclusion Rosuvastatin 10 or 20 mg is an effective and safe therapeutic option for high-risk patients to achievetheir lipid and apolipoprotein targets. (Am Heart J 2006;151:975.e12975.e9.)

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Low-density lipoprotein cholesterol (LDL-C) reduction

remains the primary target of lipid-lowering therapy to

reduce the risk of coronary heart disease (CHD).1,2

National Cholesterol Education Program Adult Treat-

ment Panel III (ATP III) guidelines recommend reduc-

tion of LDL-C to b100 mg/dL in high-risk patients.1 An

t

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From the aMethodist DeBakey Heart Center and Baylor College of Medicine, Houston,

TX, bInstituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil, cCentro Medico

Nacional de Occidente IMSS, Guadalajara, Mexico, dInstituto Medico Constituyentes,

Buenos Aires, Argentina, eMRL International, Highland Heights, KY, fMontreal Heart

Institute, Montreal, Quebec, Canada, gAndroscoggin Cardiology Associates, Auburn,

ME, and hAstraZeneca, Wilmington, DE.

Submitted September 12, 2005; accepted December 14, 2005.

Reprint requests: Christie M. Ballantyne, MD, Department of Medicine, Baylor College of

Medicine, 6565 Fannin, M.S. A-601, Houston, TX 77030.

E-mail: [email protected]

0002-8703/$ - see front matter

n 2006, Mosby, Inc. All rights reserved.

doi:10.1016/j.ahj.2005.12.013

optional LDL-C target of b70 mg/dL has been proposed

for patients with very high risk (CHD with multiple

major or uncontrolled risk factors).2 High-risk patients

frequently have elevated triglycerides (TG), with in-

creased concentration of small, dense LDL particles, an

therapeutic targets for non–high-density lipoprotein

cholesterol (non–HDL-C) and apolipoprotein (apo) B-

100 have been recommended for these individuals.1,3

Because of increasingly aggressive targets, many

patients, even among those on statin therapy, are not a

target.4 An important option to achieve targets is to

change from a less effective to a more effective statin.

In this regard, rosuvastatin has been shown to reduce

LDL-C more than many other statins.5

We examined the achievement of LDL-C targets in

high-risk patients as well as secondary non–HDL-C and

apo B targets in patients with elevated TG, when treate

with the most widely prescribed doses of atorvastatin

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Figure 1

Trial design. Treatment arms and number of patients randomized.

Table I. Demographic and baseline characteristics by period 1treatment

Characteristic, n (%) unless notedRandomized

population (n = 1993)

Male 1112 (55.8%)Age, y, mean (SD) 61.9 (10.4)z65 y 826 (41.4%)

Weight, kg, mean (SD) 87.4 (19.8)Body mass index, kg/m2, mean (SD) 30.64 (6.1)N30 kg/m2 939 (47.1%)

RaceWhite 1587 (79.6%)Hispanic 201 (10.1%)Black 156 (7.8%)Asian 32 (1.6%)Other4 17 (0.9%)

CHD or CHD risk equivalents 1235 (62.0%)Diabetes 900 (45.2%)TG z200 mg/dL 725 (36.4%)

4bOtherQ includes Native American/Alaska native, native Hawaiian/Pacificislander, and other subjects.

American Heart Journal

May 2006975.e2 Ballantyne et al

and simvastatin compared with switching to rosuvas

tin at its most widely used doses. We also report LD

reductions and changes in apolipoproteins with diffe

ent regimens of statin therapy.

MethodsTrial designThis randomized, open-label, phase IIIb trial (4522IL/006

was conducted at 152 centers in the United States, Canada

Argentina, Brazil, and Mexico in accordance with the Decl

tion of Helsinki and in compliance with the ethical princip

of good clinical practice. Appropriate ethics committees or

institutional review boards approved the trial, and all patie

provided written, informed consent before any trial procedu

Eligible patients were men and women aged z18 years wh

had (1) high risk of CHD events—documented history of C

or other established atherosclerotic disease, diabetes, or AT

III–defined 10-year CHD risk1 N20%, regardless of prior sta

treatment; (2) fasting LDL-C level z130 to b250 mg/dL (z3

to b6.46 mmol/L), based on 2 measurements within 15% o

the difference exceeded 15%, a third sample was taken and

the last 2 values used for LDL-C determination; and (3) fast

TG b400 mg/dL (b4.52 mmol/L). Exclusion criteria include

pregnancy or lactation; history of homozygous familial hyp

cholesterolemia or known hyperlipoproteinemia types I, II

IV, or V; unstable arterial disease within 3 months of trial

entry; uncontrolled hypertension; fasting serum glucose of

N180 mg/dL (N10.0 mmol/L) at any time during dietary lead

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Table II. Least-squares mean % change (SE) in lipid and apolipoprotein measures from baseline at 8 weeks

RSV 20 mg(n = 383)

ATV 10 mg(n = 389)

ATV 20 mg(n = 383)

SIM 20 mg(n = 387)

SIM 40 mg(n = 391)

LDL-CBaseline, mg/dL (SD) 167.1 (27.4) 169.0 (27.5) 168.1 (26.2) 169.4 (25.8) 168.8 (27.8)% change �52.1 (0.7) �37.1 (0.7)4 �43.3 (0.7)4 �34.2 (0.7)4 �41.2 (0.7)4

Total cholesterolBaseline, mg/dL (SD) 250.7 (32.4) 252.9 (32.5) 250.9 (32.3) 252.9 (31.3) 252.4 (31.6)% change �37.1 (0.5) �26.5 (0.5)4 �31.6 (0.5)4 �24.1 (0.5)4 �28.9 (0.5)4

TriglyceridesBaseline, mg/dL (SD) 182.0 (75.9) 184.0 (65.8) 181.3 (68.3) 183.1 (66.0) 184.9 (67.5)% change �22.8 (1.3) �17.7 (1.2)y �21.4 (1.3) �13.3 (1.2)4 �15.6 (1.2)4

HDL-CBaseline, mg/dL (SD) 47.3 (11.9) 47.2 (11.0) 46.7 (10.2) 47.0 (10.1) 46.9 (11.4)% change +6.9 (0.6) +5.3 (0.6) +3.7 (0.6)4 +5.4 (0.6) +5.9 (0.6)

Non–HDL-CBaseline, mg/dL (SD) 203.4 (33.0) 205.8 (32.5) 204.2 (32.5) 205.9 (30.4) 205.5 (32.5)% change �47.2 (0.7) �33.7 (0.6)4 �39.6 (0.7)4 �30.8 (0.6)4 �36.7 (0.6)4

LDL-C/HDL-CBaseline ratio (SD) 3.75 (1.09) 3.76 (0.99) 3.77 (1.00) 3.77 (0.94) 3.81 (1.10)% change �54.7 (0.7) �39.8 (0.7)4 �44.7 (0.7)4 �37.3 (0.7)4 �44.2 (0.7)4

Total cholesterol/HDL-CBaseline ratio (SD) 5.60 (1.43) 5.61 (1.31) 5.62 (1.33) 5.61 (1.22) 5.68 (1.42)% change �40.6 (0.6) �29.7 (0.6)4 �33.5 (0.6)4 �27.5 (0.6)4 �32.3 (0.6)4

Non–HDL-C/HDL-CBaseline ratio (SD) 4.60 (1.43) 4.61 (1.31) 4.62 (1.33) 4.61 (1.22) 4.68 (1.42)% change �50.0 (0.7) �36.4 (0.7)4 �41.1 (0.7)4 �33.7 (0.7)4 �39.7 (0.7)4

Apo BBaseline, mg/dL (SD) 159.0 (27.7) 160.6 (27.4) 160.3 (25.8) 162.6 (26.0) 161.8 (26.3)% change �40.9 (0.6) �28.9 (0.6)4 �34.9 (0.6)4 �26.8 (0.6)4 �32.2 (0.6)4

Apo A-IBaseline, mg/dL (SD) 151.4 (28.1) 151.9 (26.7) 150.4 (25.8) 152.8 (25.5) 150.8 (26.9)% change +3.8 (0.6) +3.2 (0.6) +1.3 (0.6)y +2.6 (0.6) +4.4 (0.6)

Apo B/apo A-IBaseline ratio (SD) 1.09 (0.29) 1.09 (0.26) 1.10 (0.26) 1.09 (0.24) 1.11 (0.28)% change �42.5 (0.7) �30.6 (0.7)4 �35.0 (0.7)4 �28.0 (0.7)4 �34.4 (0.7)4

Achieved LDL-C b100 mg/dLat week 8, n (%)

315 (82%) 167 (43%)4 237 (62%)4 126 (33%)4 210 (55%)4

ATV, atorvastatin; RSV, rosuvastatin; SIM, simvastatin.4Pb .0001 compared with rosuvastatin 20 mg.yPb .0125 compared with rosuvastatin 20 mg.


Volume 151, Number 5Ballantyne et al 975.e3

active liver disease or hepatic dysfunction (transaminases or

bilirubin z1.5 times upper limit of normal [ULN]); serum

creatinine of N2.0 mg/dL (N177 Amol/L); or unexplained

serum creatine kinase (CK) levels N3 times ULN.

After a 6-week dietary lead-in (discontinuation of all

cholesterol-lowering treatments and instruction in ATP III

Therapeutic Lifestyle Change Diet), eligible patients were

randomized to 1 of 5 treatment groups (Figure 1): rosuvastati

20 mg (arm 1), atorvastatin 10 mg (arm 2), atorvastatin 20 m

(arm 3), simvastatin 20 mg (arm 4), or simvastatin 40 mg (arm

5) for 8 weeks (period 1). During the 8 weeks of period 2,

patients in arm 1 continued receiving rosuvastatin 20 mg,

whereas patients in the other treatment arms either remained

on initial treatment or switched from atorvastatin 10 mg to

rosuvastatin 10 mg (arm 2), atorvastatin 20 mg to rosuvastati

20 mg (arm 3), simvastatin 20 mg to rosuvastatin 10 mg (arm 4)

and simvastatin 40 mg to rosuvastatin 20 mg (arm 5).

Efficacy analyses were performed for the intention-to-treat

population (all patients who received randomized treatment

and had a baseline and z1 postbaseline lipid measurement fo

the appropriate treatment phase), with the last observation

carried forward. Baseline lipids were the average of measure

ments at weeks �2, �1, and 0; lipids were subsequently

measured at the end of each 8-week treatment period. Primar

efficacy measure was the proportion of patients achieving

LDL-C b100 mg/dL1 at week 16. Secondary efficacy measure

included proportions of patients meeting the LDL-C target a

week 8 and changes in lipid and lipoprotein measures at

weeks 8 and 16. Supplemental analyses included proportion

of hypertriglyceridemic (TG z200 mg/dL) patients who met

both lipid targets (LDL-C b100 mg/dL; non–HDL-C

b130 mg/dL) and the suggested apo B target of b90 mg/dL3

and proportions of very high risk patients reaching the

optional LDL-C target of b70 mg/dL.2 Very high risk patients

were those with established cardiovascular disease plus one o

more of the following: multiple major risk factors, severe an

poorly controlled risk factors, and multiple risk factors of th

metabolic syndrome.

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Table III. Least-squares mean % change4 (SE) in lipid and apolipoprotein measures from baseline at 16 weeks after switching to rosuvastatinor remaining on comparator statin for 8 weeks

Treatment arm

Period 1 RSV 20 mg ATV 10 mg ATV 20 mg SIM 20 mg SIM 40 mg

Period 2RSV 20 mg(n = 362)

ATV 10 mg(n = 180)

RSV 10 mg(n = 189)

ATV 20 mg(n = 182)

RSV 20 mg(n = 184)

SIM 20 mg(n = 185)

RSV 10 mg(n = 179)

SIM 40 mg(n = 183)

RSV 20 mg(n = 183)

LDL-C% change �51.6 (0.8) �36.2 (1.1) �46.6 (1.1)y �43.4 (1.2) �50.8 (1.2)y �32.1 (1.1) �45.5 (1.1)y �39.6 (1.1) �53.7 (1.1)y

Totalcholesterol

% change �36.7 (0.6) �25.9 (0.83) �32.6 (0.8)y �31.6 (0.9) �36.5 (0.9)y �22.7 (0.9) �32.0 (0.9)y �27.6 (0.8) �38.1 (0.9)yTriglycerides

% change �21.6 (1.2) �16.2 (2.6) �17.7 (2.7) �22.0 (2.1) �20.7 (2.0) �10.9 (1.9) �18.6 (1.9)z �15.8 (1.9) �23.3 (2.0)§HDL-C

% change +7.2 (0.7) +6.1 (1.0) +7.5 (1.0) +4.0 (1.0) +5.3 (1.0) +4.3 (1.0) +6.3 (1.0) +6.9 (1.0) +7.6 (1.0)Non–HDL-C

% change �46.7 (0.7) �33.1 (1.0) �41.8 (1.0)y �39.8 (1.1) �45.7 (1.1)y �28.7 (1.1) �40.7 (1.1)y �35.3 (1.0) �48.6 (1.0)yLDL-C/HDL-C

% change �54.3 (0.8) �38.9 (1.2) �50.0 (1.2)y �44.8 (1.3) �52.6 (1.3)y �33.8 (1.3) �48.3 (1.3)y �43.2 (1.1) �56.5 (1.1)yTotal

cholesterol/HDL-C

% change �40.3 (0.7) �29.2 (1.0) �37.0 (1.1)y �33.4 (1.1) �38.8 (1.1)y �24.6 (1.1) �35.5 (1.1)y �31.7 (0.9) �41.9 (0.9)yNon–HDL-C/

HDL-C% change �49.5 (0.8) �35.7 (1.3) �45.4 (1.3)y �41.2 (1.3) �47.5 (1.3)y �30.1 (1.3) �43.6 (1.3)y �38.9 (1.0) �51.6 (1.1)y

Apo B% change �40.2 (0.7) �26.9 (1.1) �36.3 (1.1)y �35.4 (1.1) �40.4 (1.1)y �25.0 (1.0) �36.2 (1.0)y �31.4 (1.0) �42.6 (1.0)y

Apo A-I% change +4.0 (0.6) +2.5 (0.9) +4.1 (0.9) +1.2 (1.0) +3.6 (1.0) +2.1 (1.0) +3.5 (1.0) +5.1 (1.0) +5.3 (1.0)

Apo B/apo A-I% change �41.9 (0.8) �27.8 (1.1) �38.5 (1.1)y �35.4 (1.2) �41.7 (1.2)y �25.8 (1.1) �37.7 (1.1)y �34.1 (1.0) �44.9 (1.0)y

4Continuous rosuvastatin 20 mg, mean observed percent change from baseline.yP b .001 for comparisons within treatment arms.zP = .002 for comparisons within treatment arms.§P = .004 for comparisons within treatment arms.



Laboratory methodsAll laboratory samples were analyzed at a central laborat

(Medical Research Laboratories, Highland Heights, KY), as

described previously.5,6

Statistical analysisFor the primary and secondary efficacy measures assessin

cholesterol target achievement, comparisons were made

between treatment arms for period 1 and within treatment

arms for period 2 using logistic regression. Treatment and

region were fitted as factors, and baseline LDL-C was includ

as a covariate; period 1 response was fitted as a factor in per

2 analyses. Between- and within-arm comparisons of change

LDL-C and other lipid values from baseline were performed

using analysis of variance models with factors fitted for

treatment and region. Results are shown as least-squares m

percentage changes from baseline and P values from analysi

variance. The Bonferroni correction7 was applied for all per

1 comparisons for target achievement and lipid changes wit

2-sided significance level requirement of .0125. All period

pairwise comparisons had a 2-sided significance level requ

ment of .05.

Safety analysisSafety assessments included adverse event reports, clinic

laboratory data, vital signs, and physical examination. All

randomized patients receiving at least 1 dose of study

medication were included in safety analyses. Safety data w

summarized by descriptive statistics.

ResultsDemographics and baseline valuesA total of 1993 patients were randomized to 1 of

treatment groups during period 1 (Figure 1); of the

1983 received at least 1 dose of study treatment. Per

1 treatment groups were well matched with regard

demographics and baseline characteristics (Table I) a

baseline lipid levels (Table II). A total of 208 patien

(10.4%) discontinued treatment during the study

(118 during period 1 and 90 during period 2);

adverse events were the most common reason for

withdrawal, accounting for 52 patients in period 1 a

32 in period 2.

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Figure 2

Differences in incremental least-squares mean percentage changes in LDL-C between week 8 and week 16 after switching to rosuvastatin (RSV) orremaining on atorvastatin (ATV) or simvastatin (SIM) for 8 weeks. (A) Switching to RSV 10 mg vs remaining on ATV 10 mg; (B) switching to RSV20 mg vs remaining on ATV 20 mg; (C) switching to RSV 10 mg vs remaining on SIM 20 mg; (D) switching to RSV 20 mg vs remaining on SIM40 mg. 4Difference between incremental least-squares mean % changes in LDL-C from week 8 to week 16.



Changes in LDL-C levelsTable II summarizes changes from baseline in lipid an

apolipoprotein measures at 8 weeks. After 8 weeks,

rosuvastatin 20 mg reduced LDL-C more than atorvastatin

10 or 20 mg or simvastatin 20 or 40 mg (all P b .0001).

Table III summarizes those changes at 16 weeks. At

16 weeks, switching to rosuvastatin produced significan

reductions in LDL-C compared with remaining on

atorvastatin or simvastatin (all within-arm comparisons

P b .001). Figure 2 shows LDL-C values at 8 and 16 week

for both patients who remained on initial treatment and

those who switched to rosuvastatin. Switching to

rosuvastatin produced a significantly greater incrementa

percent reduction in LDL-C compared with staying on

initial therapy (all within-arm comparisons P b .001).

LDL-C target achievementThe proportion of patients who achieved the ATP II

LDL-C target of b100 mg/dL at 8 weeks on initial therap

is shown in Table II. Figure 3 shows that switching to

rosuvastatin significantly increased the proportion of

patients reaching this target at 16 weeks compared with

remaining on initial therapy (P b .001 for all compar-

isons). Differences in target achievement rates between

rosuvastatin and atorvastatin or simvastatin ranged from

15.1% to 41.7%.

A total of 1011 of the randomized patients who wer

categorized as very high risk under the 2004 advisory

addendum to the ATP III guidelines were included in th

16-week efficacy analysis. Switching to rosuvastatin

significantly increased the proportion of these patients

reaching the aggressive LDL-C target of b70 mg/dL

compared with remaining on other statins in all

treatment groups (Table IV).

Changes in other lipids and lipoproteinsAt 8 weeks, rosuvastatin 20 mg improved most lipid

measures significantly more than atorvastatin 10 or

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Figure 3

Proportions of patients achieving ATP III LDL-C goal b100 mg/dL at 16 weeks after switching to rosuvastatin (RSV) or remaining on atorvastatin(ATV) or simvastatin (SIM) after 8 weeks. 4P b .001 for within-arm comparison of rosuvastatin vs atorvastatin or simvastatin.

Table IV. Goal achievement in subgroups at 16 weeks

Treatment arm

Period 1 RSV 20 mg ATV 10 mg ATV 20 mg SIM 20 mg SIM 40 mg

Period 2RSV

20 mgATV

10 mgRSV

10 mgATV

20 mgRSV

20 mgSIM

20 mgRSV

10 mgSIM

40 mgRSV

20 mg

Very high risk patients (n = 197) (n = 98) (n = 101) (n = 100) (n = 106) (n = 100) (n = 103) (n = 94) (n = 112)LDL-C goal b70 mg/dL 37% 7% 19%4 13% 25%4 1% 17%y 10% 34%yHypertriglyceridemic patients

(TG NNNNNNNN____ 200 mg/dL)(n = 138) (n = 70) (n = 66) (n = 60) (n = 66) (n = 57) (n = 73) (n = 68) (n = 66)

LDL-C b100 mg/dL andnon–HDL-C b130 mg/dL

80% 20% 48%y 42% 61%z 19% 51%y 29% 80%y

LDL-C b100 mg/dL,non–HDL-C b130 mg/dL,and apo B b90 mg/dL

38% 3% 18%y 17% 24%§ 4% 12%t 1% 36%y

4P b .01 for within-arm comparison of rosuvastatin versus atorvastatin or simvastatin.yP b .001 for within-arm comparison of rosuvastatin versus atorvastatin or simvastatin.zP = .003 for within-arm comparison of rosuvastatin versus atorvastatin or simvastatin.§P = .035 for within-arm comparison of rosuvastatin versus atorvastatin or simvastatin.tP = .063 for within-arm comparison of rosuvastatin versus atorvastatin or simvastatin.



20 mg or simvastatin 20 or 40 mg (Table II). At

16 weeks, switching to rosuvastatin resulted in great

reductions in atherogenic lipid measures and ratios

compared with remaining on either atorvastatin or

simvastatin (all within-treatment arm comparisons

P b .001) (Table III).

LDL-C, non–HDL-C, and apo B target achievementhypertriglyceridemic patientsSignificantly greater percentages of hypertriglyceri-

demic patients reached the dual LDL-C and non–HDLtargets with rosuvastatin than with equal or higher do

of atorvastatin or simvastatin (Table IV). Meeting th

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Table V. Patients with at least 1 adverse event in period 1

Category of adverse events

Period 1 treatment

RSV 20 mg(n = 391)

ATV 10 mg(n = 400)

ATV 20 mg(n = 392)

SIM 20 mg(n = 400)

SIM 40 mg(n = 400)

Any adverse event, n (%) 150 (38.4%) 144 (36.0%) 126 (32.1%) 126 (31.5%) 152 (38.0%)Leading to death, n (%) 1 (0.3%)4 0 0 0 0Leading to withdrawal, n (%) 15 (3.8%) 12 (3.0%) 7 (1.8%) 16 (4.0%) 9 (2.3%)Serious adverse events, n (%) 6 (1.5%) 11 (2.8%) 8 (2.0%) 8 (2.0%) 4 (1.0%)

4Pulmonary embolus, not related to treatment.

Table VI. Patients with at least 1 adverse event in period 2


Period 2 treatment

RSV 10 mg(n = 372)

RSV 20 mg(n = 740)

ATV 10 mg(n = 185)

ATV 20 mg(n = 185)

SIM 20 mg(n = 188)

SIM 40 mg(n = 188)

Any adverse event, n (%) 130 (34.9%) 278 (37.6%) 60 (32.4%) 72 (38.9%) 58 (30.9%) 51 (27.1%)Leading to death, n (%) 1 (0.3%)4 0 0 0 1 (0.5%)y 0Leading to withdrawal, n (%) 9 (2.4%) 7 (0.9%) 1 (0.5%) 4 (2.2%) 1 (0.5%) 1 (0.5%)Serious adverse events, n (%) 5 (1.3%) 12 (1.6%) 4 (2.2%) 3 (1.6%) 5 (2.7%) 3 (1.6%)

4Cardiac arrest, not related to treatment.yShock, not related to treatment.



additional proposed apo B target was more difficult:

less than half of the patients who could attain the dua

LDL-C and non–HDL-C targets could meet all 3 target

(LDL-C, non–HDL-C, and apo B). In contrast, although

the fraction of hypertriglyceridemic high-risk patients

who attained the single target apo B of b90 mg/dL

was small in all treatment groups, every patient

who met this single target also attained the LDL-C

and non–HDL-C targets. Thus, the numbers of patient

who met all 3 targets are identical to those who met

the apo B target alone. More patients met all 3 target

with rosuvastatin 10 mg than with atorvastatin

10 mg or simvastatin 20 mg and with rosuvastatin

20 mg than with atorvastatin 20 mg or simvastatin

40 mg (Table IV).

SafetyAll study treatments were well tolerated, with a low

incidence of discontinuation. The frequency and type o

adverse events were comparable among all treatment

groups in both study periods (Tables V-VIII). Serum CK

elevations N10 times ULN occurred in 5 patients

(Tables VII and VIII); only 1 of these patients had muscl

symptoms (bilateral leg cramps), a patient receiving

rosuvastatin 20 mg in period 2 (1 [0.14%] of 740 patient

receiving rosuvastatin 20 mg). Treatment was discon-

tinued in this patient, with CK elevation resolving afte

discontinuation. No rhabdomyolysis was observed in

any treatment arm.

There were no symptomatic adverse events indicativ

of hepatic dysfunction. One patient had alanine ami-

notransferase elevations N3 times ULN on 2 consecutiv

measurements (Tables VII and VIII). The first measure

ment occurred during simvastatin 40 mg treatment in

period 1 and the second during rosuvastatin 20 mg

treatment in period 2. No patient had doubling of

serum creatinine from baseline. The frequency of

creatinine N30% from baseline was similar between

periods and among treatment groups and ranged from

0% (period 1, atorvastatin 20 mg) to 1.3% (period 1,

atorvastatin 10 mg). For patients with follow-up

measurements (20/23), all but 2 of these increases (on

patient on atorvastatin 10 mg and one on rosuvastatin

10 mg) either never exceeded normal limits or

recovered while on continued therapy. Overall, serum

creatinine showed a mean decrease of 2.8% (SD 9.96) t

3.8% (SD 9.60) from baseline to week 16 among

treatment groups, with no apparent differences amon

groups. Shifts in urine protein from none or trace at

baseline to z++ occurred in 9 (0.5%) of 1697 evaluate

patients during period 1, with incidence ranging from

0% (atorvastatin 10 mg) to 1.2% (atorvastatin 20 mg).

Such shifts occurred in 10 (0.6%) of 1608 patients

evaluated in period 2, with rates ranging from 0%

ne .11

Table VII. Muscle, hepatic, and renal adverse events in period 1


Period 1 treatment

RSV 20 mg(n = 391)

ATV 10 mg(n = 400)

ATV 20 mg(n = 392)

SIM 20 mg(n = 400)

SIM 40 mg(n = 400)

CK N10� ULN4 only, n (%) 1 (0.3%)y 1 (0.3%)z 0 0 0CK N10� ULN + muscle cramps, n (%) 0 0 0 0 0Rhabdomyolysis, n (%) 0 0 0 0 0ALT N3� ULN§ twice, n (%) 0 0 0 0 1 (0.3%)tCreatinine increase N30%, n (%) 3 (0.8%) 5 (1.3%) 0 4 (1.0%) 1 (0.3%)Creatinine increase N100%, n (%) 0 0 0 0 0Urine protein shift, n (%) 1/341 (0.3%) 0 4/342 (1.2%) 3/334 (0.9%) 1/348 (0.3%)

4CK 10� ULN = 1200 U/L.yCK = 2022 U/L on rosuvastatin 20 mg; patient recovered on continued therapy.zCK = 2607 U/L on atorvastatin 10 mg; patient recovered on continued therapy.§ALT 3� ULN = 75 U/L.tSame patient had 1 elevated measurement while on simvastatin 40 mg in period 1 and 1 elevated measurement on rosuvastatin 20 mg in period 2.

Table VIII. Muscle, hepatic, and renal adverse events in period 2


Period 2 treatment

RSV 10 mg(n = 372)

RSV 20 mg(n = 740)

ATV 10 mg(n = 185)

ATV 20 mg(n = 185)

SIM 20 mg(n = 188)

SIM 40 mg(n = 188)

CK N10� ULN4 only, n (%) 0 1 (0.1%)y 0 1 (0.5%)z 0 0CK N10� ULN + muscle cramps, n (%) 0 1 (0.1%)§ 0 0 0 0Rhabdomyolysis, n 0 0 0 0 0 0ALT N3� ULNt twice, n (%) 0 1 (0.1%)b 0 0 0 0Creatinine increase N30%, n (%) 3 (0.8%) 4 (0.5%) 2 (1.1%) 1 (0.6%) 2 (1.1%) 2 (1.1%)Creatinine increase N100%, n (%) 0 0 0 0 0 0Urine protein shift, n (%) 2/318 (0.6%) 4/653 (0.6%) 1/153 (0.7%) 1/163 (0.6%) 2/163 (1.2%) 0

4CK 10� ULN=1200 U/L.yCK = 1826 U/L on rosuvastatin 20 mg; patient recovered off therapy.zCK = 4210 U/L on atorvastatin 20 mg; patient recovered off therapy.§CK = 1211 U/L on rosuvastatin 20 mg; patient recovered off therapy with withdrawal from the randomized study.tALT 3� ULN = 75 U/L.bSame patient had 1 elevated measurement while on simvastatin 40 mg in period 1 and 1 elevated measurement on rosuvastatin 20 mg in period 2.



(simvastatin 40 mg) to 1.2% (simvastatin 20 mg). No

of the increases in proteinuria were associated with

renal impairment.

as

of

L

s

id

a-

L.

ed

ing

DiscussionAchievement of LDL-C targets in high-risk patients h

been a challenging objective in clinical practice,8

particularly with the recommendation of even lower

targets in very high risk patients based on evidence

clinical benefit.1-3,9,10 The LDL-C target of b100 mg/d

in high-risk patients and the optional LDL-C target of

b70 mg/dL in very high risk patients are beyond the

scope of many older-generation statins even with

maximum doses in patients with elevated LDL-C. Thi

study examined the 3 most effective statins at their

starting or moderate doses,5 representing over three

quarters of the dosages prescribed in clinical practice

Results showed how difficult it is for some of these

regimens to achieve the recommended or optional

LDL-C targets.

High-risk hypertriglyceridemic patients have dual lip

targets: LDL-C b100 mg/dL (primary) and non–HDL-C

b130 mg/dL (secondary). In these patients, an altern

tive secondary apo B target of b90 mg/dL might be

representative of the dual lipid targets.3 This study

shows that the two alternatives are not equivalent.

Achieving an apo B of b90 mg/dL in patients with

elevated TG was much more difficult than achieving

both LDL-C b100 mg/dL and non–HDL-C b130 mg/d

Conversely, achieving an apo B of b90 mg/dL guarante

achieving the dual LDL-C and non–HDL-C targets.

Switching from statins that are less effective in

reducing LDL-C, particularly when they are approach

-

)

y

,

f

r

-

f

,-

tfg

y

e

r

tsts

n



their maximal dose, to those that are more effective

in their lower dose range constitutes an important

treatment option for optimizing achievement of ATP III

goals in high-risk patients. This trial showed that switch

ing from the most commonly used doses of atorvastatin

or simvastatin to rosuvastatin at the recommended

starting dose (10 mg) or optional starting dose (20 mg

is an effective strategy for improving LDL-C and non–

HDL-C target achievement. Switching to rosuvastatin

also led to greater achievement of the proposed apo B

target in hypertriglyceridemic patients. The magnitude

of the benefit achieved with switching to rosuvastatin

in these high-risk patients is consistent with treatment

differences observed in comparative trials of rosuva-

statin and other statins at commonly used doses.5,12

In this study, there were no clinically relevant differ-

ences among the statins in adverse events or propensit

for causing skeletal muscle toxicity, hepatic impairment

or renal dysfunction over the relatively short duration o

treatment. Similar safety findings have been reported in

other comparative trials involving rosuvastatin and othe

statins at currently approved doses,12-15 and in long-term

follow-up studies of rosuvastatin patients.16 Adding to

the documented efficacy and safety of the 10-mg start

dose, the data in this large trial reinforce that rosuva-

statin 20 mg is an effective and safe therapeutic option

for patients who need to achieve their lipid and

apolipoprotein targets.

We thank Joe Hirsch, from BioScience Communica

tions, who provided medical writing support on behal

of AstraZeneca.

.)d

lt

.

References1. National Cholesterol Education Program Adult Treatment Panel III

Third report of the National Cholesterol Education Program (NCEPExpert Panel on Detection, Evaluation, and Treatment of High BlooCholesterol in Adults (Adult Treatment Panel III) final report.Circulation 2002;106:3143 -421.

2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recentclinical trials for the National Cholesterol Education Program AduTreatment Panel III guidelines. Circulation 2004;110:227 -39.

3. Grundy SM. Low-density lipoprotein, non–high-density lipoproteinand apolipoprotein B as targets of lipid-lowering therapy. Circulation 2002;106:2526-9.

4. Pearson TA, Laroura I, Chu H, et al. The Lipid Treatment AssessmenProject (L-TAP): a multicenter survey to evaluate the percentages odyslipidemic patients receiving lipid-lowering therapy and achievinlow-density lipoprotein cholesterol goals. Arch Intern Med2000;160:459-67.

5. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacand safety of rosuvastatin versus atorvastatin, simvastatin, andpravastatin across doses (STELLAR Trial). Am J Cardiol2003;92:152 -60.

6. Steiner P, Freidel J, Bremmer W, et al. Standardization of micro-methods for plasma cholesterol, triglyceride and HDL-cholesterolwith the clinics’ methodology [abstract]. J Clin Chem Biochem1981;19:850 -1.

7. Miller RG Jr. Simultaneous statistical inference. 2nd ed. New York(NY): Springer-Verlag; 1981.

8. Sueta CA, Chowdhury M, Boccuzzi SJ, et al. Analysis of the degreof undertreatment of hyperlipidemia and congestive heart failuresecondary to coronary artery disease. Am J Cardiol 1999;83:1303 -7.

9. Third Joint Task Force of European and other Societies onCardiovascular Disease Prevention in Clinical Practice. Executivesummary. European guidelines on cardiovascular disease preven-tion in clinical practice. Eur Heart J 2003;24:1601 -10.

10. Genest J, Frolich J, Foder G, et al. Recommendations for themanagement of dyslipidemia and the prevention of cardiovasculadisease: summary of the 2003 update. CMAJ 2003;169:921 -4.

11. IMS National Prescription Audit, April 2004-March 2005.12. Schneck DW, Knopp RH, Ballantyne CM, et al. Comparative effec

of rosuvastatin and atorvastatin across their dose ranges in patienwith hypercholesterolemia and without active arterial disease.Am J Cardiol 2003;91:33 -41.

13. Schuster H, Barter PJ, Stender S, et al. Effects of switching statins oachievement of lipid goals: Measuring Effective Reductions inCholesterol Using Rosuvastatin Therapy (MERCURY I) study. AmHeart J 2004;147:705 -12.

14. Olsson AG, Istad H, Luurila O, et al. Effects of rosuvastatin andatorvastatin compared over 52 weeks of treatment in patients withhypercholesterolemia. Am Heart J 2002;144:1044 -51.

15. Shepherd J, Hunninghake DB, Stein EA, et al. Safety of rosuvastatinAm J Cardiol 2004;94:882 -8.

16. Barter P, Taylor R, Ditmarsch M, et al. Measuring effectivereductions in cholesterol using rosuvastatin therapy (MERCURY I):safety analysis from an open-label extension. Atheroscler Suppl2005;6:101 [Abstract W16-P-005].

DESCRIPTION

CRESTOR® (rosuvastatin calcium) is a synthetic lipid-loweringagent. Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglu-taryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzesthe conversion of HMG-CoA to mevalonate, an early andrate-limiting step in cholesterol biosynthesis.

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. Theempirical formula for rosuvastatin calcium is(C22H27FN3O6S)2Ca.Its molecular weight is 1001.14. Its structural formula is:

Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble inethanol. Rosuvastatin is a hydrophilic compound with a partitioncoefficient (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:microcrystalline cellulose NF, lactose monohydrate NF, tribasiccalcium phosphate NF, crospovidone NF, magnesium stearate NF,hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferricoxide, and red ferric oxide NF.

CLINICAL PHARMACOLOGY

General: In the bloodstream, cholesterol and triglycerides (TG)circulate as part of lipoprotein complexes. With ultracentrifuga-tion, these complexes separate into very-low-density lipoprotein(VLDL), intermediate-density lipoprotein (IDL), and low-densitylipoprotein (LDL) fractions that contain apolipoprotein B-100(ApoB-100) and high-density lipoprotein (HDL) fractions.

Cholesterol and TG synthesized in the liver are incorporated intoVLDL and secreted into the circulation for delivery to peripheraltissues. TG are removed by the action of lipases, and in a seriesof steps, the modified VLDL is transformed first into IDL and theninto cholesterol-rich LDL. IDL and LDL are removed from thecirculation mainly by high affinity ApoB/E receptors, which areexpressed to the greatest extent on liver cells. HDL is hypothe-sized to participate in the reverse transport of cholesterol fromtissues back to the liver.

Epidemiologic, experimental, and clinical studies have estab-lished that high LDL cholesterol (LDL-C), low HDL cholesterol(HDL-C), and high plasma TG promote human atherosclerosisand are risk factors for developing cardiovascular disease. Incontrast, higher levels of HDL-C are associated with decreasedcardiovascular risk.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins,including VLDL, IDL, and remnants, can also promote atheroscle-rosis. Elevated plasma triglycerides are frequently found with lowHDL-C levels and small LDL particles, as well as in associationwith non-lipid metabolic risk factors for coronary heart disease(CHD). As such, total plasma TG has not consistently been shownto be an independent risk factor for CHD. Furthermore, the inde-pendent effect of raising HDL or lowering TG on the risk ofcoronary and cardiovascular morbidity and mortality has notbeen determined.

Mechanism of Action: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limitingenzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A tomevalonate, a precursor of cholesterol. In vivo studies in animals,and in vitro studies in cultured animal and human cells haveshown rosuvastatin to have a high uptake into, and selectivity for,action in the liver, the target organ for cholesterol lowering. Inin vivo and in vitro studies, rosuvastatin produces its lipid-modi-fying effects in two ways. First, it increases the number of hepaticLDL receptors on the cell-surface to enhance uptake and catabo-

lism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

Rosuvastatin reduces total cholesterol (total-C), LDL-C, ApoB,and nonHDL-C (total cholesterol minus HDL-C) in patients withhomozygous and heterozygous familial hypercholesterolemia(FH), nonfamilial forms of hypercholesterolemia, and mixeddyslipidemia. Rosuvastatin also reduces TG and producesincreases in HDL-C. Rosuvastatin reduces total-C, LDL-C, VLDL-cholesterol (VLDL-C), ApoB, nonHDL-C and TG, and increasesHDL-C in patients with isolated hypertriglyceridemia. The effectof rosuvastatin on cardiovascular morbidity and mortality has notbeen determined.

Pharmacokinetics and Drug MetabolismAbsorption: In clinical pharmacology studies in man, peakplasma concentrations of rosuvastatin were reached 3 to 5 hoursfollowing oral dosing. Both peak concentration (Cmax) and areaunder the plasma concentration-time curve (AUC) increased inapproximate proportion to rosuvastatin dose. The absolutebioavailability of rosuvastatin is approximately 20%.

Administration of rosuvastatin with food decreased the rate ofdrug absorption by 20% as assessed by Cmax, but there was noeffect on the extent of absorption as assessed by AUC.

Plasma concentrations of rosuvastatin do not differ followingevening or morning drug administration.

Significant LDL-C reductions are seen when rosuvastatin is givenwith or without food, and regardless of the time of day of drugadministration.

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

Metabolism: Rosuvastatin is not extensively metabolized;approximately 10% of a radiolabeled dose is recovered asmetabolite. The major metabolite is N-desmethyl rosuvastatin,which is formed principally by cytochrome P450 2C9, and in vitrostudies have demonstrated that N-desmethyl rosuvastatin hasapproximately one-sixth to one-half the HMG-CoA reductaseinhibitory activity of rosuvastatin. Overall, greater than 90% ofactive plasma HMG-CoA reductase inhibitory activity isaccounted for by rosuvastatin.

Excretion: Following oral administration, rosuvastatin and itsmetabolites are primarily excreted in the feces (90%). The elimi-nation 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.

Special PopulationsRace: A population pharmacokinetic analysis revealed no clini-cally relevant differences in pharmacokinetics among Caucasian,Hispanic, and Black or Afro-Caribbean groups. However, pharma-cokinetic studies, including one conducted in the US, havedemonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group. (See WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, General and DOSAGE ANDADMINISTRATION.)

Gender: There were no differences in plasma concentrations ofrosuvastatin between men and women.

Geriatric: There were no differences in plasma concentrations ofrosuvastatin between the nonelderly and elderly populations (ageM65 years).

Pediatric: In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with heterozygous FH receivedsingle and multiple oral doses of rosuvastatin. Both Cmax andAUC of rosuvastatin were similar to values observed in adultsubjects administered the same doses.

Renal Insufficiency: Mild to moderate renal impairment (creati-nine clearance M30 mL/min/1.73m2) had no influence on plasmaconcentrations of rosuvastatin when oral doses of 20 mg rosuva-statin were administered for 14 days. However, plasmaconcentrations of rosuvastatin increased to a clinically significantextent (about 3-fold) in patients with severe renal impairment(CLcr l30 mL/min/1.73m2) compared with healthy subjects(CLcr L80 mL/min/1.73m2) (see PRECAUTIONS, General).

Hemodialysis: Steady-state plasma concentrations of rosuva-statin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects withnormal renal function.

Hepatic Insufficiency: In patients with chronic alcohol liverdisease, plasma concentrations of rosuvastatin were modestly

increased. In patients with Child-Pugh A disease, Cmax and AUCwere increased by 60% and 5%, respectively, as compared withpatients with normal liver function. In patients with Child-Pugh Bdisease, Cmax and AUC were increased 100% and 21%, respec-tively, compared with patients with normal liver function (seeCONTRAINDICATIONS and WARNINGS, Liver Enzymes).

Drug-Drug Interactions Cytochrome P450 3A4: In vitro and in vivo data indicate thatrosuvastatin clearance is not dependent on metabolism bycytochrome P450 3A4 to a clinically significant extent. This hasbeen confirmed in studies with known cytochrome P450 3A4inhibitors (ketoconazole, erythromycin, itraconazole).

Ketoconazole: Coadministration of ketoconazole (200 mg twicedaily for 7 days) with rosuvastatin (80 mg) resulted in no changein plasma concentrations of rosuvastatin.

Erythromycin: Coadministration of erythromycin (500 mg fourtimes daily for 7 days) with rosuvastatin (80 mg) decreased AUCand Cmax of rosuvastatin by 20% and 31%, respectively. Thesereductions are not considered clinically significant.

Itraconazole: Itraconazole (200 mg once daily for 5 days)resulted in a 39% and 28% increase in AUC of rosuvastatin after10 mg and 80 mg dosing, respectively. These increases are notconsidered clinically significant.

Fluconazole: Coadministration of fluconazole (200 mg once dailyfor 11 days) with rosuvastatin (80 mg) resulted in a 14% increasein AUC of rosuvastatin. This increase is not considered clinicallysignificant.

Cyclosporine: Coadministration of cyclosporine with rosuva-statin resulted in no significant changes in cyclosporine plasmaconcentrations. However, Cmax and AUC of rosuvastatinincreased 11- and 7-fold, respectively, compared with historicaldata in healthy subjects. These increases are considered to be clinically significant (see PRECAUTIONS, Drug Interactions,WARNINGS, Myopathy/Rhabdomyolysis, and DOSAGE ANDADMINISTRATION).

Warfarin: Coadministration of warfarin (25 mg) with rosuvastatin(40 mg) did not change warfarin plasma concentrations butincreased the International Normalized Ratio (INR) (see PRECAU-TIONS, Drug Interactions).

Digoxin: Coadministration of digoxin (0.5 mg) with rosuvastatin(40 mg) resulted in no change to digoxin plasma concentrations.

Fenofibrate: Coadministration of fenofibrate (67 mg three timesdaily) with rosuvastatin (10 mg) resulted in no significantchanges in plasma concentrations of rosuvastatin or fenofibrate(see PRECAUTIONS, Drug Interactions, and WARNINGS,Myopathy/Rhabdomyolysis).

Gemfibrozil: Coadministration of gemfibrozil (600 mg twice dailyfor 7 days) with rosuvastatin (80 mg) resulted in a 90% and120% increase for AUC and Cmax of rosuvastatin, respectively.This increase is considered to be clinically significant (seePRECAUTIONS, Drug Interactions, WARNINGS, Myopathy/Rhabdomyolysis, DOSAGE AND ADMINISTRATION).

Ezetimibe: Coadministration of ezetimibe (10 mg ) with rosuva-statin (40 mg) resulted in no significant changes in plasmaconcentrations of rosuvastatin or ezetimibe.

Antacid: Coadministration of an antacid (aluminum and mag-nesium hydroxide combination) with rosuvastatin (40 mg)resulted in a decrease in plasma concentrations of rosuvastatinby 54%. However, when the antacid was given 2 hours after rosuvastatin, there were no clinically significant changes inplasma concentrations of rosuvastatin (see PRECAUTIONS,Information for Patients).

Oral contraceptives: Coadministration of oral contraceptives(ethinyl estradiol and norgestrel) with rosuvastatin resulted in anincrease in plasma concentrations of ethinyl estradiol andnorgestrel by 26% and 34%, respectively.

Lopinavir/Ritonavir: Coadministration of CRESTOR and a combi-nation product of two protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers was associated with anapproximately 2-fold and 5-fold increase in rosuvastatin steady-state AUC(0-24) and Cmax respectively. Interactions betweenCRESTOR and other protease inhibitors have not been examined.(See PRECAUTIONS, Drug Interactions.)

Clinical Studies

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Type IIa and IIb) CRESTOR reduces total-C, LDL-C, ApoB, nonHDL-C, and TG, andincreases HDL-C, in patients with hypercholesterolemia and

CRESTOR® (rosuvastatin calcium) Tablets CRESTOR® (rosuvastatin calcium) Tablets

Ca2+

F

OH OH O

O

SO2Me

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N

N

2

mixed dyslipidemia. Therapeutic response is seen within 1 week,and maximum response is usually achieved within 4 weeks andmaintained during long-term therapy.

CRESTOR is effective in a wide variety of adult patient popula-tions with hypercholesterolemia, with and without hyper-triglyceridemia, regardless of race, gender, or age and in specialpopulations such as diabetics or patients with heterozygous FH.Experience in pediatric patients has been limited to patients withhomozygous FH.

Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with hyper-cholesterolemia, CRESTOR given as a single daily dose for6 weeks significantly reduced total-C, LDL-C, nonHDL-C, andApoB, across the dose range (Table 1).

Table 1. Dose-Response in Patients With Primary Hypercholesterolemia

(Adjusted Mean % Change From Baseline at Week 6)

Dose N Total-C LDL-C NonHDL-C ApoB TG HDL-C

Placebo 13 -5 -7 -7 -3 -3 3

5 17 -33 -45 -44 -38 -35 13

10 17 -36 -52 -48 -42 -10 14

20 17 -40 -55 -51 -46 -23 8

40 18 -46 -63 -60 -54 -28 10

Active-Controlled Study: CRESTOR was compared with theHMG-CoA reductase inhibitors atorvastatin, simvastatin, andpravastatin in a multicenter, open-label, dose-ranging study of2,240 patients with Type IIa and IIb hypercholesterolemia. Afterrandomization, patients were treated for 6 weeks with a singledaily dose of either CRESTOR, atorvastatin, simvastatin, orpravastatin (Figure 1 and Table 2).

Figure 1. Percent LDL-C Change by Dose of CRESTOR, Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Patients With Type IIa/IIb Dyslipidemia

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 2. Percent Change in LDL-C From Baseline to Week 6(LS means §) by Treatment Group

(sample sizes ranging from 156-167 patients per group)

Treatment Daily DoseTreatment 10 mg 20 mg 40 mg 80 mg

CRESTOR -46* -52† -55‡ —

Atorvastatin -37 -43 -48 -51

Pravastatin -20 -24 -30 —

Simvastatin -28 -35 -39 -46* 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. (pl0.002)

† CRESTOR 20 mg reduced LDL-C significantly more than atorvastatin 20 mgand 40 mg; pravastatin 20 mg and 40 mg; simvastatin 20 mg, 40 mg, and 80 mg. (pl0.002)

‡ CRESTOR 40 mg reduced LDL-C significantly more than atorvastatin 40 mg; pravastatin 40 mg; simvastatin 40 mg and 80 mg (pl0.002)

§ Corresponding standard errors are approximately 1.00

Heterozygous Familial HypercholesterolemiaIn a study of patients with heterozygous FH (baseline mean LDLof 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 eachdose in both treatment groups (Table 3).

Table 3. Mean LDL-C Percentage Change From Baseline CRESTOR Atorvastatin(n=435) (n=187)

LS Mean* (95% CI) 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%)* LS Means are least square means adjusted for baseline LDL.

Hypertriglyceridemia (Fredrickson Type IIb & IV)In a double-blind, placebo-controlled dose-response study inpatients with baseline TG levels from 273 to 817 mg/dL,CRESTOR given as a single daily dose (5 to 40 mg) over 6 weekssignificantly reduced serum TG levels (Table 4).

Table 4. Dose-Response in Patients With PrimaryHypertriglyceridemia Over 6 Weeks Dosing

Median (Min, Max) Percent Change From Baseline

CRESTOR CRESTOR CRESTOR CRESTORDose Placebo 5 mg 10 mg 20 mg 40 mg

N = 26 N = 25 N = 23 N = 27 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)

Homozygous Familial Hypercholesterolemia In an open-label, forced-titration study, homozygous FH patients(n=40, 8-63 years) were evaluated for their response toCRESTOR 20 to 40 mg titrated at a 6-week interval. In the overallpopulation, the mean LDL-C reduction from baseline was 22%.About one-third of the patients benefited from increasing theirdose from 20 mg to 40 mg with further LDL lowering of greaterthan 6%. In the 27 patients with at least a 15% reduction in LDL-C, the mean LDL-C reduction was 30% (median 28% reduc-tion). Among 13 patients with an LDL-C reduction of l15%, 3 had no change or an increase in LDL-C. Reductions in LDL-C of15% or greater were observed in 3 of 5 patients with knownreceptor negative status.

INDICATIONS AND USAGE

CRESTOR is indicated:

1. as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB,nonHDL-C, and TG levels and to increase HDL-C in patientswith primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type IIaand IIb);

2. as an adjunct to diet for the treatment of patients with elevatedserum TG levels (Fredrickson Type IV);

3. to reduce LDL-C, total-C, and ApoB in patients with homo-zygous familial hypercholesterolemia as an adjunct to otherlipid-lowering treatments (e.g., LDL apheresis) or if such treat-ments are unavailable.

According to NCEP-ATP III guidelines, therapy with lipid-alteringagents should be a component of multiple-risk-factor interven-tion in individuals at increased risk for coronary heart disease dueto hypercholesterolemia. The two major modalities of LDL-lowering therapy are therapeutic lifestyle changes (TLC) and drugtherapy. The TLC Diet stresses reductions in saturated fat andcholesterol intake. Table 5 defines LDL-C goals and cutpoints forinitiation of TLC and for drug consideration.

Table 5. NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle

Changes and Drug Therapy in Different Risk CategoriesRisk Category LDL Goal LDL level at which LDL level at which to

to initiate TLC consider drug therapy

CHDa or l100 mg/dL M100 mg/dL M130 mg/dLCHD Risk Equivalent (100-129 mg/dL:(10-year risk L20%) drug optional)b

2+ Risk Factors l130 mg/dL M130 mg/dL M130 mg/dL(10-year risk m20%) 10-year risk 10-20%

M160 mg/dL10-year risk l10%

0-1 Risk Factorc l160 mg/dL M160 mg/dL M190 mg/dL (160-189 mg/dL)

(LDL-lowering drug optional)a CHD = coronary heart disease.b Some authorities recommend use of LDL-lowering drugs in this category if

an LDL-C l100 mg/dL cannot be achieved by TLC. Others prefer use ofdrugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid orfibrate. Clinical judgment also may call for deferring drug therapy in thissubcategory.

c Almost all people with 0-1 risk factor have 10-year risk l10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.

After the LDL-C goal has been achieved, if the TG is still M200 mg/dL, nonHDL-C (total-C minus HDL-C) becomes asecondary target of therapy. NonHDL-C goals are set 30 mg/dLhigher than LDL-C goals for each risk category.

At the time of hospitalization for a coronary event, considerationcan be given to initiating drug therapy at discharge if the LDL-C isM130 mg/dL (see NCEP Treatment Guidelines, above).

Patients L20 years of age should be screened for elevatedcholesterol levels every 5 years.

Prior to initiating therapy with CRESTOR, secondary causes forhypercholesterolemia (e.g., poorly-controlled diabetes mellitus,hypothyroidism, nephrotic syndrome, dyslipoproteinemias,obstructive liver disease, other drug therapy, and alcoholism)should be excluded, and a lipid profile performed to measuretotal-C, LDL-C, HDL-C, and TG. For patients with TGl 400 mg/dL(l4.5 mmol/L), LDL-C can be estimated using the followingequation: LDL-C = total-C – (0.20 x [TG] + HDL-C). For TG levels L400 mg/dL (L4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined byultracentrifugation.

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

CONTRAINDICATIONS

CRESTOR is contraindicated in patients with a known hyper-sensitivity to any component of this product.

Rosuvastatin is contraindicated in patients with active liverdisease or with unexplained persistent elevations of serumtransaminases (see WARNINGS, Liver Enzymes).

Pregnancy and LactationAtherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on theoutcome of long-term therapy of primary hypercholesterolemia.Cholesterol and other products of cholesterol biosynthesis areessential components for fetal development (including synthesisof steroids and cell membranes). Since HMG-CoA reductaseinhibitors decrease cholesterol synthesis and possibly thesynthesis of other biologically active substances derived fromcholesterol, they may cause fetal harm when administered topregnant women. Therefore, HMG-CoA reductase inhibitors arecontraindicated during pregnancy and in nursing mothers.ROSUVASTATIN SHOULD BE ADMINISTERED TO WOMEN OFCHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLYUNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THEPOTENTIAL HAZARDS. If the patient becomes pregnant whiletaking this drug, therapy should be discontinued immediately andthe patient apprised of the potential hazard to the fetus.

WARNINGS

Liver EnzymesHMG-CoA reductase inhibitors, like some other lipid-loweringtherapies, have been associated with biochemical abnormalitiesof liver function. The incidence of persistent elevations (L3 timesthe upper limit of normal [ULN] occurring on 2 or more consecu-tive occasions) in serum transaminases in fixed dose studies was0.4, 0, 0, and 0.1% in patients who received rosuvastatin 5, 10,20, and 40 mg, respectively. In most cases, the elevations weretransient and resolved or improved on continued therapy or aftera brief interruption in therapy. There were two cases of jaundice,for which a relationship to rosuvastatin therapy could not bedetermined, which resolved after discontinuation of therapy.There were no cases of liver failure or irreversible liver disease inthese trials.

It is recommended that liver function tests be performed beforeand at 12 weeks following both the initiation of therapy and anyelevation of dose, and periodically (e.g., semiannually) there-after. Liver enzyme changes generally occur in the first 3 monthsof treatment with rosuvastatin. Patients who develop increasedtransaminase levels should be monitored until the abnormalitieshave resolved. Should an increase in ALT or AST of L3 timesULN persist, reduction of dose or withdrawal of rosuvastatin isrecommended.

Rosuvastatin should be used with caution in patients whoconsume substantial quantities of alcohol and/or have a historyof liver disease (see CLINICAL PHARMACOLOGY, SpecialPopulations, Hepatic Insufficiency). Active liver disease or unex-plained persistent transaminase elevations are contraindicationsto the use of rosuvastatin (see CONTRAINDICATIONS).

Myopathy/RhabdomyolysisRare cases of rhabdomyolysis with acute renal failuresecondary to myoglobinuria have been reported with rosuva-statin and with other drugs in this class.

Uncomplicated myalgia has been reported in rosuvastatin-treatedpatients (see ADVERSE REACTIONS). Creatine kinase (CK) eleva-tions (L10 times upper limit of normal) occurred in 0.2% to

CRESTOR® (rosuvastatin calcium) TabletsCRESTOR® (rosuvastatin calcium) Tablets CRESTOR® (rosuvastatin calcium) Tablets

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CRESTOR Atorvastatin PravastatinSimvastatin1020 40 1020 40 80 20 40 80 10 20 40

0.4% of patients taking rosuvastatin at doses of up to 40 mg inclinical studies. Treatment-related myopathy, defined as muscleaches or muscle weakness in conjunction with increases in CKvalues L10 times upper limit of normal, was reported in up to0.1% of patients taking rosuvastatin doses of up to 40 mg in clinical studies. In clinical trials, the incidence of myopathy andrhabdomyolysis increased at doses of rosuvastatin above therecommended dosage range (5 to 40 mg). In postmarketingexperience, effects on skeletal muscle, e.g. uncomplicatedmyalgia, myopathy and, rarely, rhabdomyolysis have beenreported in patients treated with HMG-CoA reductase inhibitorsincluding rosuvastatin. As with other HMG-CoA reductaseinhibitors, reports of rhabdomyolysis with rosuvastatin are rare,but higher at the highest marketed dose (40 mg). Factors thatmay predispose patients to myopathy with HMG-CoA reductaseinhibitors include advanced age (M65 years), hypothyroidism,and renal insufficiency.

Consequently:1. Rosuvastatin should be prescribed with caution in patients

with predisposing factors for myopathy, such as, renal impair-ment (see DOSAGE AND ADMINISTRATION), advanced age,and inadequately treated hypothyroidism.

2. Patients should be advised to promptly report unexplainedmuscle pain, tenderness, or weakness, particularly if accompa-nied by malaise or fever. Rosuvastatin therapy should bediscontinued if markedly elevated CK levels occur or myopathyis diagnosed or suspected.

3. The 40 mg dose of rosuvastatin is reserved only for thosepatients who have not achieved their LDL-C goal utilizing the 20 mg dose of rosuvastatin once daily (see DOSAGE ANDADMINISTRATION).

4. The risk of myopathy during treatment with rosuvastatin maybe increased with concurrent administration of other lipid-lowering therapies or cyclosporine, (see CLINICAL PHAR-MACOLOGY, Drug Interactions, PRECAUTIONS, DrugInteractions, and DOSAGE AND ADMINISTRATION). Thebenefit of further alterations in lipid levels by the combineduse of rosuvastatin with fibrates or niacin should be carefullyweighed against the potential risks of this combination.Combination therapy with rosuvastatin and gemfibrozilshould generally be avoided. (See DOSAGE AND ADMINIS-TRATION and PRECAUTIONS, Drug Interactions).

5. The risk of myopathy during treatment with rosuvastatin maybe increased in circumstances which increase rosuvastatindrug levels (see CLINICAL PHARMACOLOGY, SpecialPopulations, Race and Renal Insufficiency, and PRECAU-TIONS, General).

6. Rosuvastatin therapy should also be temporarily withheld inany patient with an acute, serious condition suggestive ofmyopathy or predisposing to the development of renalfailure secondary to rhabdomyolysis (e.g., sepsis, hypoten-sion, dehydration, major surgery, trauma, severe metabolic,endocrine, and electrolyte disorders, or uncontrolledseizures).

PRECAUTIONS

GeneralBefore instituting therapy with rosuvastatin, an attempt should bemade to control hypercholesterolemia with appropriate diet andexercise, weight reduction in obese patients, and treatment ofunderlying medical problems (see INDICATIONS AND USAGE).

Administration of rosuvastatin 20 mg to patients with severerenal impairment (CLcr l30 mL/min/1.73 m2) resulted in a 3-foldincrease in plasma concentrations of rosuvastatin compared withhealthy volunteers (see WARNINGS, Myopathy/Rhabdomyolysisand DOSAGE AND ADMINISTRATION).

The result of a large pharmacokinetic study conducted in the USdemonstrated an approximate 2-fold elevation in median exposure in Asian subjects (having either Filipino, Chinese,Japanese, Korean, Vietnamese or Asian-Indian origin) comparedwith a Caucasian control group. This increase should be consid-ered when making rosuvastatin dosing decisions for Asian patients. (See WARNINGS, Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Special Populations, Race, andDOSAGE AND ADMINISTRATION.)

Information for PatientsPatients should be advised to report promptly unexplainedmuscle pain, tenderness, or weakness, particularly if accompa-nied by malaise or fever.

When taking rosuvastatin with an aluminum and magnesiumhydroxide combination antacid, the antacid should be taken atleast 2 hours after rosuvastatin administration (see CLINICALPHARMACOLOGY, Drug Interactions).

Laboratory TestsIn the rosuvastatin clinical trial program, dipstick-positiveproteinuria and microscopic hematuria were observed amongrosuvastatin-treated patients, predominantly in patients dosedabove the recommended dose range (i.e., 80 mg). However, thisfinding was more frequent in patients taking rosuvastatin 40 mg,when compared to lower doses of rosuvastatin or comparatorstatins, though it was generally transient and was not associatedwith worsening renal function. Although the clinical significanceof this finding is unknown, a dose reduction should be consid-ered for patients on rosuvastatin 40 mg therapy with unexplainedpersistent proteinuria during routine urinalysis testing.

Drug InteractionsCyclosporine: When rosuvastatin 10 mg was coadministeredwith cyclosporine in cardiac transplant patients, rosuvastatinmean Cmax and mean AUC were increased 11-fold and 7-fold,respectively, compared with healthy volunteers. These increasesare considered to be clinically significant and require specialconsideration in the dosing of rosuvastatin to patients takingconcomitant cyclosporine (see WARNINGS, Myopathy/Rhabdomyolysis, and DOSAGE AND ADMINISTRATION).

Warfarin: Coadministration of rosuvastatin to patients on stablewarfarin therapy resulted in clinically significant rises in INR (L4,baseline 2-3). In patients taking coumarin anticoagulants androsuvastatin concomitantly, INR should be determined beforestarting rosuvastatin and frequently enough during early therapyto ensure that no significant alteration of INR occurs. Once astable INR time has been documented, INR can be monitored atthe intervals usually recommended for patients on coumarin anti-coagulants. If the dose of rosuvastatin is changed, the sameprocedure should be repeated. Rosuvastatin therapy has notbeen associated with bleeding or with changes in INR in patientsnot taking anticoagulants.

Gemfibrozil: Coadministration of a single rosuvastatin dose tohealthy volunteers on gemfibrozil (600 mg twice daily) resulted ina 2.2- and 1.9-fold, respectively, increase in mean Cmax and meanAUC of rosuvastatin (see DOSAGE AND ADMINISTRATION).

Lopinavir/Ritonavir: Coadministration of CRESTOR and a combi-nation product of two protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers was associated with anapproximately 2-fold and 5-fold increase in rosuvastatin steady-state AUC(0-24) and Cmax respectively. These increases should beconsidered when initiating and titrating CRESTOR in patients withHIV taking lopinavir/ritonavir.

Endocrine FunctionAlthough clinical studies have shown that rosuvastatin alonedoes not reduce basal plasma cortisol concentration or impairadrenal reserve, caution should be exercised if any HMG-CoAreductase inhibitor or other agent used to lower cholesterol levelsis administered concomitantly with drugs that may decrease thelevels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

CNS ToxicityCNS vascular lesions, characterized by perivascular hemor-rhages, edema, and mononuclear cell infiltration of perivascularspaces, have been observed in dogs treated with several othermembers of this drug class. A chemically similar drug in thisclass produced dose-dependent optic nerve degeneration(Wallerian degeneration of retinogeniculate fibers) in dogs, at adose that produced plasma drug levels about 30 times higherthan the mean drug level in humans taking the highest recom-mended dose. Edema, hemorrhage, and partial necrosis in theinterstitium of the choroid plexus was observed in a female dogsacrificed 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 comparisons). Corneal opacity wasseen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage(systemic exposures 20 times the human exposure at 40 mg/daybased on AUC comparisons). Cataracts were seen in dogs treatedfor 12 weeks by oral gavage at 30 mg/kg/day (systemic expo-sures 60 times the human exposure at 40 mg/day based on AUCcomparisons). Retinal dysplasia and retinal loss were seen indogs 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 m30 mg/kg/day (systemicexposures m60 times the human exposure at 40 mg/day basedon AUC comparisons) following treatment up to one year, did notreveal retinal findings.

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 expo-sure at 40 mg/day based on AUC. Increased incidence of polypswas 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 hepato-cellular adenoma/carcinoma was observed at 200 mg/kg/day atsystemic exposures 20 times human exposure at 40 mg/daybased on AUC. An increased incidence of hepatocellular tumorswas not seen at lower doses.

Rosuvastatin was not mutagenic or clastogenic with or withoutmetabolic activation in the Ames test with Salmonellatyphimurium and Escherichia coli, the mouse lymphoma assay,and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mousemicronucleus test.

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to andthroughout mating and females were treated 2 weeks prior tomating and throughout mating until gestation day 7. No adverseeffect on fertility was observed at 50 mg/kg/day (systemic expo-sures up to 10 times human exposure at 40 mg/day based onAUC comparisons). In testicles of dogs treated with rosuvastatinat 30 mg/kg/day for one month, spermatidic giant cells wereseen. Spermatidic giant cells were observed in monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation ofseminiferous tubular epithelium. Exposures in the dog were 20times and in the monkey 10 times human exposure at 40 mg/daybased on body surface area comparisons. Similar findings havebeen seen with other drugs in this class.

PregnancyPregnancy Category X See CONTRAINDICATIONS.

Rosuvastatin may cause fetal harm when administered to a preg-nant woman. Rosuvastatin is contraindicated in women who areor may become pregnant. Safety in pregnant women has notbeen established. There are no adequate and well-controlledstudies of rosuvastatin in pregnant women. Rosuvastatin crossesthe placenta and is found in fetal tissue and amniotic fluid at 3%and 20%, respectively, of the maternal plasma concentrationfollowing a single 25 mg/kg oral gavage dose on gestation day 16in rats. A higher fetal tissue distribution (25% maternal plasmaconcentration) was observed in rabbits after a single oral gavagedose of 1 mg/kg on gestation day 18. If this drug is administeredto a woman with reproductive potential, the patient should beapprised of the potential hazard to a fetus.

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

In pregnant rats given oral gavage doses of 2, 10, 50 mg/kg/dayfrom gestation day 7 through lactation day 21 (weaning),decreased pup survival occurred in groups given 50 mg/kg/day,systemic exposures M12 times human exposure at 40 mg/daybased on body surface area comparisons.

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

Rosuvastatin was not teratogenic in rats at m25 mg/kg/day or inrabbits m3 mg/kg/day (systemic exposures equivalent to humanexposure at 40 mg/day based on AUC or body surface compar-ison, respectively).

Nursing MothersIt is not known whether rosuvastatin is excreted in human milk.Studies in lactating rats have demonstrated that rosuvastatin issecreted into breast milk at levels 3 times higher than thatobtained in the plasma following oral gavage dosing. Becausemany drugs are excreted in human milk and because of thepotential for serious adverse reactions in nursing infants fromrosuvastatin, a decision should be made whether to discontinuenursing or administration of rosuvastatin taking into account theimportance of the drug to the lactating woman.

Pediatric UseThe safety and effectiveness in pediatric patients have not beenestablished. Treatment experience with rosuvastatin in a pediatricpopulation is limited to 8 patients with homozygous FH. None ofthese patients was below 8 years of age.


Geriatric UseOf the 10,275 patients in clinical studies with rosuvastatin, 3,159(31%) were 65 years and older, and 698 (6.8%) were 75 yearsand older. The overall frequency of adverse events and types ofadverse events were similar in patients above and below 65 yearsof age. (See WARNINGS, Myopathy/Rhabdomyolysis.)

The efficacy of rosuvastatin in the geriatric population (M65years of age) was comparable to the efficacy observed in the non-elderly.

ADVERSE REACTIONSRosuvastatin is generally well tolerated. Adverse reactions have usually been mild and transient. In clinical studies of 10,275 patients, 3.7% were discontinued due to adverse experiences attributable to rosuvastatin. The most frequentadverse events thought to be related to rosuvastatin weremyalgia, constipation, asthenia, abdominal pain, and nausea.

Clinical Adverse ExperiencesAdverse experiences, regardless of causality assessment,reported in M2% of patients in placebo-controlled clinical studiesof rosuvastatin are shown in Table 6; discontinuations due toadverse events in these studies of up to 12 weeks durationoccurred in 3% of patients on rosuvastatin and 5% on placebo.

Table 6. Adverse Events in Placebo-Controlled Studies Rosuvastatin Placebo

Adverse event N=744 N=382

Pharyngitis 9.0 7.6

Headache 5.5 5.0

Diarrhea 3.4 2.9

Dyspepsia 3.4 3.1

Nausea 3.4 3.1

Myalgia 2.8 1.3

Asthenia 2.7 2.6

Back pain 2.6 2.4

Flu syndrome 2.3 1.8

Urinary tract infection 2.3 1.6

Rhinitis 2.2 2.1

Sinusitis 2.0 1.8

In addition, the following adverse events were reported, regard-less of causality assessment, in M1% of 10,275 patients treatedwith rosuvastatin in clinical studies. The events in italics occurredin M2% of these patients.

Body as a Whole: Abdominal pain, accidental injury, chest pain,infection, pain, pelvic pain, and neck pain.

Cardiovascular System: Hypertension, angina pectoris, vaso-dilatation, and palpitation.

Digestive System: Constipation, gastroenteritis, vomiting, flatulence, periodontal abscess, and gastritis.

Endocrine: Diabetes mellitus.

Hemic and Lymphatic System: Anemia and ecchymosis.

Metabolic and Nutritional Disorders: Peripheral edema.

Musculoskeletal System: Arthritis, arthralgia, and pathologicalfracture.

Nervous System: Dizziness, insomnia, hypertonia, paresthesia,depression, anxiety, vertigo, and neuralgia.

Respiratory System: Bronchitis, cough increased, dyspnea,pneumonia, and asthma.

Skin and Appendages: Rash and pruritus.

Laboratory Abnormalities: In the rosuvastatin clinical trialprogram, dipstick-positive proteinuria and microscopic hema-turia were observed among rosuvastatin-treated patients,predominantly in patients dosed above the recommended doserange (i.e., 80 mg). However, this finding was more frequent inpatients taking rosuvastatin 40 mg, when compared to lowerdoses of rosuvastatin or comparator statins, though it was gener-ally transient and was not associated with worsening renalfunction. (See PRECAUTIONS, Laboratory Tests.)

Other abnormal laboratory values reported were elevated creatinephosphokinase, transaminases, hyperglycemia, glutamyltranspeptidase, alkaline phosphatase, bilirubin, and thyroid function abnormalities.

Other adverse events reported less frequently than 1% in therosuvastatin clinical study program, regardless of causalityassessment, included arrhythmia, hepatitis, hypersensitivity reactions (i.e., face edema, thrombocytopenia, leukopenia,vesiculobullous rash, urticaria, and angioedema), kidney failure,syncope, myasthenia, myositis, pancreatitis, photosensitivityreaction, myopathy, and rhabdomyolysis.

Postmarketing ExperienceIn addition to the events reported above, as with other drugs in this class, the following event has been reported during post-marketing experience with CRESTOR, regardless of causalityassessment: very rare cases of jaundice and memory loss.

OVERDOSAGEThere is no specific treatment in the event of overdose. In theevent of overdose, the patient should be treated symptomaticallyand supportive measures instituted as required. Hemodialysisdoes not significantly enhance clearance of rosuvastatin.

DOSAGE AND ADMINISTRATIONThe patient should be placed on a standard cholesterol-loweringdiet before receiving CRESTOR and should continue on this dietduring treatment. CRESTOR can be administered as a single doseat any time of day, with or without food.

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia(Fredrickson Type IIa and IIb)The dose range for CRESTOR is 5 to 40 mg once daily. Therapywith CRESTOR should be individualized according to goal oftherapy and response. The usual recommended starting dose ofCRESTOR is 10 mg once daily. However, initiation of therapy with5 mg once daily should be considered for patients requiring lessaggressive LDL-C reductions, who have predisposing factors formyopathy, and as noted below for special populations such aspatients taking cyclosporine, Asian patients, and patients withsevere renal insufficiency (see CLINICAL PHARMACOLOGY,Race, and Renal Insufficiency, and Drug Interactions). Forpatients with marked hypercholesterolemia (LDL-C L190 mg/dL)and aggressive lipid targets, a 20-mg starting dose may beconsidered. After initiation and/or upon titration of CRESTOR,lipid levels should be analyzed within 2 to 4 weeks and dosageadjusted accordingly.

The 40-mg dose of CRESTOR is reserved only for those patientswho have not achieved their LDL-C goal utilizing the 20 mgdose of CRESTOR once daily (see WARNINGS, Myopathy/Rhabdomyolysis). When initiating statin therapy or switchingfrom another statin therapy, the appropriate CRESTOR startingdose should first be utilized, and only then titrated according tothe patient’s individualized goal of therapy.

Homozygous Familial HypercholesterolemiaThe recommended starting dose of CRESTOR is 20 mg once dailyin patients with homozygous FH. The maximum recommendeddaily dose is 40 mg. CRESTOR should be used in these patientsas an adjunct to other lipid-lowering treatments (e.g., LDLapheresis) or if such treatments are unavailable. Response totherapy should be estimated from pre-apheresis LDL-C levels.

Dosage in Asian PatientsInitiation of CRESTOR therapy with 5 mg once daily should beconsidered for Asian patients. The potential for increasedsystemic exposures relative to Caucasians is relevant whenconsidering escalation of dose in cases where hypercholes-terolemia is not adequately controlled at doses of 5, 10, or 20 mgonce daily. (See WARNINGS, Myopathy/Rhabdomyolysis, CLINICAL PHARMACOLOGY, Special Populations, Race, andPRECAUTIONS, General).

Dosage in Patients Taking CyclosporineIn patients taking cyclosporine, therapy should be limited toCRESTOR 5 mg once daily (see WARNINGS, Myopathy/Rhabdomyolysis, and PRECAUTIONS, Drug Interactions).

Concomitant Lipid-Lowering Therapy The effect of CRESTOR on LDL-C and total-C may be enhancedwhen used in combination with a bile acid binding resin. IfCRESTOR is used in combination with gemfibrozil, the dose of CRESTOR should be limited to 10 mg once daily (see WARN-INGS, Myopathy/Rhabdomyolysis, and PRECAUTIONS, DrugInteractions).

Dosage in Patients With Renal InsufficiencyNo modification of dosage is necessary for patients with mild tomoderate renal insufficiency. For patients with severe renalimpairment (CLcr l30 mL/min/1.73 m2) not on hemodialysis,dosing of CRESTOR should be started at 5 mg once daily and notto exceed 10 mg once daily (see PRECAUTIONS, General, andCLINICAL PHARMACOLOGY, Special Populations, RenalInsufficiency).

HOW SUPPLIEDCRESTOR® (rosuvastatin calcium) Tablets are supplied as:

5 mg tablets: Yellow, round, biconvex, coated tablets identified as“CRESTOR” and “5” debossed on one side and plain on the other

side of the tablet.(NDC 0310-0755-90) bottles of 90

10 mg tablets: Pink, round, biconvex, coated tablets identified as“CRESTOR” and “10” debossed on one side and plain on theother side of the tablet.

(NDC 0310-0751-90) bottles of 90(NDC 0310-0751-39) unit dose packages of 100

20 mg tablets: Pink, round, biconvex, coated tablets identified as“CRESTOR” and “20” debossed on one side and plain on theother side of the tablet.

(NDC 0310-0752-90) bottles of 90(NDC 0310-0752-39) unit dose packages of 100

40 mg tablets: Pink, oval, biconvex, coated tablets identified as“CRESTOR” debossed on one side and “40” debossed on theother side of the tablet.

(NDC 0310-0754-30) bottles of 30

StorageStore at controlled room temperature, 20-25°C (68-77°F) [seeUSP]. Protect from moisture.

Rx only

CRESTOR is a trademark of the AstraZeneca group of companies© AstraZeneca 2003, 2005, 2007Licensed from SHIONOGI & CO., LTD., Osaka, Japan

Manufactured for:AstraZeneca Pharmaceuticals LPWilmington, DE 19850By: IPR Pharmaceuticals, Inc.Carolina, PR 00984

PCC 63030330043-02Rev 01/07 248272


email: [email protected]

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