Mechanism Of Action
CRESTOR is a selective and competitive inhibitor of HMG-CoA
reductase, the rate-limiting enzyme that converts 3-hydroxy3methylglutaryl
coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in
animals, and in vitro studies in cultured animal and human cells have shown
rosuvastatin to have a high uptake into, and selectivity for, action in the
liver, the target organ for cholesterol lowering. In in vivo and in vitro
studies, rosuvastatin produces its lipid-modifying effects in two ways. First,
it increases the number of hepatic LDL receptors on the cell-surface to enhance
uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis
of VLDL, which reduces the total number of VLDL and LDL particles.
In clinical pharmacology studies in man, peak plasma
concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing.
Both Cmax and AUC increased in approximate proportion to CRESTOR dose. The
absolute bioavailability of rosuvastatin is approximately 20%.
Administration of CRESTOR with food did not affect the AUC
The AUC of rosuvastatin does not differ following evening or
morning drug administration.
Mean volume of distribution at steady-state of rosuvastatin
is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins,
mostly albumin. This binding is reversible and independent of plasma concentrations.
Rosuvastatin is not extensively metabolized; approximately
10% of a radiolabeled dose is recovered as metabolite. The major metabolite is
N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9,
and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately
one-sixth to one-half the HMGCoA reductase inhibitory activity of the
parent compound. Overall, greater than 90% of active plasma HMGCoA
reductase inhibitory activity is accounted for by the parent compound.
Following oral administration, rosuvastatin and its
metabolites are primarily excreted in the feces (90%). The elimination
half-life (t½) 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.
A population pharmacokinetic analysis revealed no clinically
relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black
or Afro-Caribbean groups. However, pharmacokinetic studies, including one
conducted in the US, have demonstrated an approximate 2fold elevation
in median exposure (AUC and Cmax) in Asian subjects when compared with a
Caucasian control group.
There were no differences in plasma concentrations of
rosuvastatin between men and women.
In a population pharmacokinetic analysis of two pediatric
trials involving patients with heterozygous familial hypercholesterolemia 10 to
17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure
appeared comparable to or lower than rosuvastatin exposure in adult patients.
There were no differences in plasma concentrations of
rosuvastatin between the nonelderly and elderly populations (age ≥ 65
Mild to moderate renal impairment (CLcr ≥ 30
mL/min/1.73 m²) had no influence on plasma concentrations of rosuvastatin.
However, plasma concentrations of rosuvastatin increased to a clinically significant
extent (about 3fold) in patients with severe renal impairment (CLcr
< 30 mL/min/1.73 m²) not receiving hemodialysis compared with healthy
subjects (CLcr > 80 mL/min/1.73 m²).
Steady-state plasma concentrations of rosuvastatin in
patients on chronic hemodialysis were approximately 50% greater compared with
healthy volunteer subjects with normal renal function.
In patients with chronic alcohol liver disease, plasma
concentrations of rosuvastatin were modestly increased.
In patients with ChildPugh A disease, Cmax and AUC
were increased by 60% and 5%, respectively, as compared with patients with
normal liver function. In patients with ChildPugh B disease, Cmax and
AUC were increased 100% and 21%, respectively, compared with patients with
normal liver function.
Rosuvastatin clearance is not dependent on metabolism by
cytochrome P450 3A4 to a clinically significant extent.
Rosuvastatin is a substrate for certain transporter proteins
including the hepatic uptake transporter organic anion-transporting polyprotein
1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP).
Concomitant administration of CRESTOR with medications that are inhibitors of
these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors)
may result in increased rosuvastatin plasma concentrations and an increased
risk of myopathy [see DOSAGE AND ADMINISTRATION]. It is recommended that
prescribers consult the relevant product information when considering administration
of such products together with CRESTOR.
Table 4: Effect of Coadministered Drugs on Rosuvastatin
|Coadministered drug and dosing regimen
(ratio with/without coadministered drug)
No Effect = 1.0
|Change in AUC
||Change in Cmax
|Cyclosporine - stable dose required
(75 mg -200 mg BID)
|10 mg QD for 10 days
|Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days
|Simeprevir 150 mg QD, 7 days
||10 mg, single dose
|Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days
||20 mg QD for 7 days
|Gemfibrozil 600 mg BID for 7 days
|Eltrombopag 75 mg QD, 5 days
|Darunavir 600 mg/ritonavir 100 mg BID, 7 days
||10 mg QD for 7 days
|Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days
|Dronedarone 400 mg BID
|Itraconazole 200 mg QD, 5 days
||10 mg or 80 mg
|Ezetimibe 10 mg QD, 14 days
||10 mg QD for 14 days
|Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days
|Fenofibrate 67 mg TID for 7 days
|Rifampicin 450 mg QD, 7 days
|Aluminum & magnesium hydroxide combination antacid Administered simultaneously Administered 2 hours apart
||40 mg 40 mg
|Ketoconazole 200 mg BID for 7 days
|Fluconazole 200 mg QD for 11 days
|Erythromycin 500 mg QID for 7 days
|*Single dose unless otherwise noted.
†Clinically significant [see DOSAGE AND ADMINISTRATION and WARNINGS
‡Mean ratio with 90% CI
(with/without coadministered drug, e.g., 1 = no change,
0.7 = 30% decrease, 11 = 11 fold increase in exposure)
Table 5: Effect of Rosuvastatin Coadministration on
Systemic Exposure to Other Drugs
|Rosuvastatin Dosage Regimen
|Name and Dose
||Mean Ratio (ratio with/without
coadminis tered drug)
No Effect = 1.0
|Change in AUC
||Change in Cmax
|40 mg QD for 10 days
||Warfarin* 25 mg single dose
||R- Warfarin 1.0 (1.0-1.1)†
S-Warfarin 1.1 (1.0-1.1)†
|R-Warfarin 1.0 (0.9-1.0)†
S-Warfarin 1.0 (0.9-1.1)†
|40 mg QD for 12 days
||Digoxin 0.5 mg single dose
|40 mg QD for 28 days
||Oral Contraceptive (ethinyl estradiol 0.035 mg & norgestrel 0.180, 0.215 and 0.250 mg) QD for 21 Days
||EE 1.3 (1.2-1.3)†
NG 1.3 (1.3-1.4)†
|EE 1.3 (1.2-1.3)†
NG 1.2 (1.1-1.3)†
|*Clinically significant pharmacodynamic effects [see WARNINGS
†Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change,
0.7=30% decrease, 11=11-fold increase in exposure)
Disposition of HMG-CoA reductase inhibitors, including
rosuvastatin, involves OATP1B1 and other transporter proteins. Higher plasma
concentrations of rosuvastatin have been reported in very small groups of
patients (n=3 to 5) who have two reduced function alleles of the gene that
encodes OATP1B1 (SLCO1B1 521T > C). The frequency of this genotype (i.e.,
SLCO1B1 521 C/C) is generally lower than 5% in most racial/ethnic groups. The
impact of this polymorphism on efficacy and/or safety of rosuvastatin has not
been clearly established.
Animal Toxicology And/Or Pharmacology
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).Â 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.
Juvenile Toxicology Study
In a juvenile study, rats were dosed by oral gavage with 10
or 50 mg/kg/day from weaning for 9 weeks prior to pairing, throughout pairing
and up to the day before necropsy for males or up to gestation day 7 for
females. No effects on sexual development, testicular and epididymal appearance
or fertility were observed at either dose level (2 times or up to 24 times the
human exposure (AUC) at the maximum pediatric dose of 20 mg/day).
Hyperlipidemia And Mixed Dyslipidemia
CRESTOR reduces TotalC, LDLC, ApoB,
nonHDLC, and TG, and increases HDLC, 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
TotalC, LDLC, nonHDLC, and ApoB, across the dose
range (Table 6).
Table 6: Dose-Response in Patients with Hyperlipidemia
(Adjusted Mean % Change from Baseline at Week 6)
|CRESTOR 5 mg
|CRESTOR 10 mg
|CRESTOR 20 mg
|CRESTOR 40 mg
Active-Controlled Study: CRESTOR was compared with
the HMGCoA reductase inhibitors atorvastatin, simvastatin, and
pravastatin in a multicenter, open-label, dose-ranging study of 2240 patients
with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated
for 6 weeks with a single daily dose of either CRESTOR, atorvastatin,
simvastatin, or pravastatin (Figure 1 and Table 7).
Figure 1: Percent LDLC Change by Dose of
CRESTOR, Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Patients with
Hyperlipidemia or Mixed 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 LDLC: 189 mg/dL
Table 7: Percent Change in LDL-C From Baseline to Week 6
(LS Mean*) by Treatment Group (Sample Sizes Ranging from 156-167 Patients Per
||Treatment Daily Dose
|*Corresponding standard errors are approximately 1.00.
†CRESTOR 10 mg reduced LDL-C significantly more than atorvastatin 10 mg;
pravastatin 10 mg, 20 mg, and 4 0mg; simvastatin 10 mg, 20 mg, and 4 0 mg.
(p < 0.002)
‡CRESTOR 20 mg reduced LDL-C significantly more than atorvastatin 20 mg and 4 0
mg; pravastatin 20 mg and4 0 mg; simvastatin 20 mg, 4 0 mg, and 80 mg. (p <
§CRESTOR 4 0 mg reduced LDL-C significantly more than atorvastatin 4 0 mg;
pravastatin 4 0 mg; simvastatin 4 0 mg, and 80 mg. (p < 0.002)
Heterozygous Familial Hypercholesterolemia
Active-Controlled Study: In a study of patients with
heterozygous FH (baseline mean LDL of 291), patients were randomized to CRESTOR
20 mg or atorvastatin 20 mg. The dose was increased by 6- week intervals.
Significant LDL-C reductions from baseline were seen at each dose in both
treatment groups (Table 8).
Table 8: Mean LDL-C Percentage Change from Baseline
(n=435) LS Mean (95% CI)
(n=187) LS Mean (95% CI)
|* LS Means are least square means adjusted for baseline
Dose-Response Study: In a double-blind,
placebo-controlled dose-response study in patients with baseline TG levels from
273 to 817 mg/dL, CRESTOR given as a single daily dose (5 to 40 mg) over 6
weeks significantly reduced serum TG levels (Table 9).
Table 9: Dose-Response in Patients with Primary
Hypertriglyceridemia over 6 Weeks Dosing Median (Min, Max) Percent Change from
|CRESTOR 5 mg
|CRESTOR 10 mg
|CRESTOR 20 mg
|CRESTOR 40 mg
Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
In a randomized, multicenter, double-blind crossover study,
32 patients (27 with ε2/ε2 and 4 with apo E mutation [Arg145Cys]
with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) entered a 6-week
dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet.
Following dietary lead-in, patients were randomized to a sequence of treatments
in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed
by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg.
CRESTOR reduced non HDLC (primary end point) and circulating remnant lipoprotein
levels. Results are shown in the table below.
Table 10: Lipid-modifying Effects of Rosuvastatin 10 mg
and 20 mg in Primary Dysbetalipoproteinemia (Type III hyperlipoproteinemia)
After Six Weeks by Median Percent Change (95% CI) from Baseline (N=32)
||Median at Baseline (mg/dL)
||Median percent change from baseline (95% CI) CRESTOR 10 mg
||Median percent change from baseline (95% CI) CRESTOR 20 mg
(-46.9, - 37.5)
Homozygous Familial Hypercholesterolemia
Dose-Titration Study: In an open-label,
forced-titration study, homozygous FH patients (n=40, 863 years) were
evaluated for their response to CRESTOR 20 to 40 mg titrated at a
6week interval. In the overall population, the mean LDLC
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 LDLC,
the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with
an LDLC reduction of < 15%, 3 had no change or an increase in
LDLC. Reductions in LDLC of 15% or greater were observed in
3 of 5 patients with known receptor negative status.
Pediatric Patients With Homozygous Familial Hypercholesterolemia
CRESTOR was studied in a randomized, double-blind,
placebo-controlled, multicenter, cross-over study in 14 children and
adolescents with homozygous familial hypercholesterolemia. The study included a
4-week dietary lead-in phase during which patients received CRESTOR 10 mg
daily, a cross-over phase that included two 6-week treatment periods with
either CRESTOR 20 mg or placebo in random order, followed by a 12-week
open-label phase during which all patients received CRESTOR 20 mg. Patients
ranged in age from 7 to 15 years of age (median 11 years), 50% were male, 71%
were Caucasian, 21% were Asian, 7% were Black, and no patients were of Hispanic
ethnicity. Fifty percent were on apheresis therapy and 57% were taking
ezetimibe. Patients who entered the study on apheresis therapy or ezetimibe
continued the treatment throughout the entire study. Mean LDL-C at baseline was
416 mg/dL (range 152 to 716 mg/dL). A total of 13 patients completed both
treatment periods of the randomized cross-over phase; one patient withdrew
consent due to inability to have blood drawn during the cross-over phase.
CRESTOR 20 mg significantly reduced LDL-C, total cholesterol,
ApoB, and non-HDL-C compared to placebo (Table 11).
Table 11: Lipid-modifying Effects of Rosuvastatin in
Pediatric Patients 7 to 15 years of Age with Homozygous Familial Hypercholesterolemia
After 6 Weeks
|CRESTOR 20 mg
|Percent difference (95% CI)
|% Difference estimates are based on transformations of the
estimated mean difference in log LDL measurements between CRESTOR and placebo
using a mixed model adjusted for study period
1p=0.005, 2p=0.003, 3p=0.024
Pediatric Patients With Heterozygous Familial Hypercholesterolemia
In a double-blind, randomized, multicenter,
placebo-controlled, 12 week study, 176 (97 male and 79 female) children and
adolescents with heterozygous familial hypercholesterolemia were randomized to rosuvastatin
5, 10 or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years
(median age of 14 years) with approximately 30% of the patients 10 to 13 years
and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V,
respectively. Females were at least 1 year postmenarche. Mean LDL-C at baseline
was 233 mg/dL (range of 129 to 399). The 12-week double blind phase was followed
by a 40-week open label dose-titration phase, where all patients (n=173)
received 5 mg, 10 mg or 20 mg rosuvastatin daily.
Rosuvastatin significantly reduced LDL-C (primary end point),
total cholesterol and ApoB levels at each dose compared to placebo. Results are
shown in Table 12 below.
Table 12: Lipid-Modifying Effects of Rosuvastatin in
Pediatric Patients 10 to 17 years of Age with Heterozygous Familial
Hypercholesterolemia (Least-Squares Mean Percent Change from Baseline to Week
|*Median percent change
†Difference from placebo not statistically significant
At the end of the 12-week, double blind treatment period,
the percentage of patients achieving the LDLC goal of less than 110 mg/dL (2.8
mmol/L) was 0% for placebo, 12% for rosuvastatin 5 mg, 41% for rosuvastatin 10
mg and 41% for rosuvastatin 20 mg. For the 40-week, open-label phase, 71% of
the patients were titrated to the maximum dose of 20 mg and 41% of the patients
achieved the LDL-C goal of 110 mg/dL.
Rosuvastatin was also studied in a two year open-label,
uncontrolled, titration to goal trial that included 175 children and
adolescents with heterozygous familial hypercholesterolemia who were 8 to 17
years old (79 boys and 96 girls). All patients had a documented genetic defect
in the LDL receptor or in Apo B. Approximately 89% were Caucasian, 7% were
Asian, 1% were Black, and fewer than 1% were Hispanic. Mean LDL-C at baseline
was 236 mg/dL. Fifty-eight (33%) patients were prepubertal at baseline. The
starting rosuvastatin dosage for all children and adolescents was 5 mg once
daily. Children 8 to less than 10 years of age (n=41 at baseline) could titrate
to a maximum dosage of 10 mg once daily, and children and adolescents 10 to 17
years of age could titrate to a maximum dosage of 20 mg once daily.
The reductions in LDL-C from baseline were generally
consistent across age groups within the trial as well as with previous
experience in both adult and pediatric controlled trials.
The long-term efficacy of rosuvastatin therapy initiated in
childhood to reduce morbidity and mortality in adulthood has not been
Slowing Of The Progression Of Atherosclerosis
In the Measuring Effects on Intima Media Thickness: an Evaluation
Of Rosuvastatin 40 mg (METEOR) study, the effect of therapy with CRESTOR on
carotid atherosclerosis was assessed by B-mode ultrasonography in patients with
elevated LDLC, at low risk (Framingham risk < 10% over ten years) for
symptomatic coronary artery disease and with subclinical atherosclerosis as
evidenced by carotid intimal-medial thickness (cIMT). In this double-blind,
placebo-controlled clinical study 984 patients were randomized (of whom 876
were analyzed) in a 5:2 ratio to CRESTOR 40 mg or placebo once daily.
Ultrasonograms of the carotid walls were used to determine the annualized rate
of change per patient from baseline to two years in mean maximum cIMT of 12
measured segments. The estimated difference in the rate of change in the
maximum cIMT analyzed over all 12 carotid artery sites between patients treated
with CRESTOR and placebo-treated patients was -0.0145 mm/year (95% CI - 0.0196,
- 0.0093; p < 0.0001).
The annualized rate of change from baseline for the placebo
group was +0.0131 mm/year (p < 0.0001). The annualized rate of change from
baseline for the group treated with CRESTOR was -0.0014 mm/year (p=0.32).
At an individual patient level in the group treated with
CRESTOR, 52.1% of patients demonstrated an absence of disease progression
(defined as a negative annualized rate of change), compared to 37.7% of patients
in the placebo group.
Primary Prevention Of Cardiovascular Disease
In the Justification for the Use of Statins in Primary
Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the
effect of CRESTOR (rosuvastatin calcium) on the occurrence of major
cardiovascular (CV) disease events was assessed in 17,802 men ( ≥ 50 years)
and women ( ≥ 60 years) who had no clinically evident cardiovascular
disease, LDLC levels < 130 mg/dL (3.3 mmol/l) and hsCRP
levels ≥ 2 mg/L. The study population had an estimated baseline coronary
heart disease risk of 11.6% over 10 years based on the Framingham risk criteria
and included a high percentage of patients with additional risk factors such as
hypertension (58%), low HDLC levels (23%), cigarette smoking (16%),
or a family history of premature CHD (12%). Study participants had a median
baseline LDLC of 108 mg/dL and hsCRP of 4.3 mg/L. Study participants
were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily
(n=8901) and were followed for a mean duration of 2 years. The JUPITER study
was stopped early by the Data Safety Monitoring Board due to meeting predefined
stopping rules for efficacy in rosuvastatin-treated subjects. The primary end
point was a composite end point consisting of the time-to-first occurrence of
any of the following major CV events: CV death, nonfatal myocardial infarction,
nonfatal stroke, hospitalization for unstable angina or an arterial
Rosuvastatin significantly reduced the risk of major CV
events (252 events in the placebo group vs. 142 events in the rosuvastatin
group) with a statistically significant (p < 0.001) relative risk reduction
of 44% and absolute risk reduction of 1.2% (see Figure 2). The risk reduction
for the primary end point was consistent across the following predefined
subgroups: age, sex, race, smoking status, family history of premature CHD,
body mass index, LDLC, HDLC, and hsCRP levels.
Figure 2: Time to First Occurrence of Major
Cardiovascular Events in JUPITER
The individual components of the primary end point are
presented in Figure 3. Rosuvastatin significantly reduced the risk of nonfatal
myocardial infarction, nonfatal stroke, and arterial revascularization procedures.
There were no significant treatment differences between the rosuvastatin and
placebo groups for death due to cardiovascular causes or hospitalizations for
Rosuvastatin significantly reduced the risk of myocardial
infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects
vs. 9 fatal events and 22 nonfatal events in rosuvastatin-treated events in
placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in
rosuvastatin-treated subjects) and the risk of stroke (6 fatal events and 58
nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal
events in rosuvastatin-treated subjects).
In a post-hoc subgroup analysis of JUPITER subjects (n=1405;
rosuvastatin=725, placebo=680) with a hsCRP ≥ 2 mg/L and no other
traditional risk factors (smoking, BP ≥ 140/90 or taking
antihypertensives, low HDLC) other than age, after adjustment for
high HDLC, there was no significant treatment benefit with
Figure 3: Major CV Events by Treatment Group in JUPITER
At one year, rosuvastatin increased HDLC and
reduced LDLC, hsCRP, total cholesterol and serum triglyceride levels
(p < 0.001 for all versus placebo).