Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00016
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Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: October 2003
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Bibliographic ID: UF00087345
Volume ID: VID00016
Source Institution: University of Florida
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Warnitra Wimberly, Pharm.D. Candidate

The American Heart Association estimates
there are 102.3 million American adults with total
cholesterol values of 200 mg/dL or higher and 41.3
million that have levels greater than 240 mg/dL.1
Although there are numerous medications available
for the treatment of hypercholesterolemia, the station
class is the most effective in lowering low-density
lipoprotein cholesterol (LDL-C). Multiple clinical
trials have demonstrated their ability to reduce mor-
bidity and mortality. Rosuvastatin (Crestor) is
the newest station that has demonstrated larger re-
ductions in LDL-C than the current stations on the
market. It was approved by the Food and Drug Ad-
ministration (FDA) on August 12, 2003 for the
treatment of hypercholesterolemia and is manufac-
tured by AstraZeneca. This article will explore the
pharmacology, pharmacokinetics, safety, and effi-
cacy of rosuvastatin.

Lipid Metabolism
Cholesterol and triglycerides (TG) are syn-
thesized in the liver and are incorporated into very
low-density lipoproteins (VLDLs) that are secreted
into the circulation for delivery to peripheral tis-
sues. Because cholesterol and TG are not soluble in
water, they circulate together as a lipid and protein
complex (lipoprotein) in the blood. This complex

is composed of particles of VLDL, intermediate-
density lipoprotein (IDL) and LDL. Triglycerides
are removed by lipases, while the modified VLDL
is transformed into an IDL and then into the choles-
terol rich LDL. The LDL particle contains apolipo-
protein B-100 (ApoB-100) and fractions of high-
density lipoprotein (HDL), which is thought to fa-
cilitate the reverse transport of cholesterol from tis-
sues back to the liver.2

Pharmacology and Pharmacokinetics
Rosuvastatin is a selective and competitive
inhibitor of hydroxymethyl glutaryl coenzyme
(HMG-CoA) reductase, the rate limiting enzyme
that converts 3 HMG-CoA to mevalonate, a precur-
sor of cholesterol. Rosuvastatin decreases lipids
through two main mechanisms: 1) it increases the
number of hepatic LDL receptors on the cell sur-
face to increase uptake and breakdown of LDL and
2) it inhibits hepatic synthesis of VLDL, which re-
duces the total number of VLDL and LDL parti-
cles. Rosuvastatin increases HDL and reduces total
cholesterol, LDL, Apo B, TG, and non-HDL in pa-
tients with homozygous and heterozygous familial
hypercholesterolemia, non-familial forms of hyper-
cholesterolemia, and mixed dyslipidemias.34
Rosuvastatin's peak plasma concentration



INDEX FOR VOLUME 18 (OCT. 2002-SEP. 2003)
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Table 1. Dose-response to rosuvastatin in patients with primary hypercholesterolemia7
Dose N Total-C* LDL-C* ApoB* TG* HDL-C*
Placebo 29 -2+1 -4+2 -22 -15 4+2
5 17 -3+2t -43+2t -37+2 -35+7 14+3
10 16 -35+2t -51+2t -412 -107 14+3
20 13 -402t -573t -493 -238 10+4
40 34 -46+1 -63+2t -541 -285t 10+2
80 31 -47+2t -65+2t -552 -236 13+3
N=number of patients, Total-C total cholesterol, LDL-C low density lipoprotein cholesterol, ApoB apolipoprotein B, TG triglycerides, HDL-C high density
lipoprotein cholesterol.
*Values are the percent change from baseline at week 6 expressed as least-squares mean SE. p<0.001 compared with placebo. p<0.05 compared with placebo.

(Cmax) and area under the curve (AUC) increase in a
dose-dependent manner. Following an oral dose,
the Cmax is reached in 3 to 5 hours, with an absolute
bioavailability of about 20%. Food may delay the
rate but not the extent of absorption of rosuvastatin.
When given with food, peak plasma concentrations
decreased by up to 20% while the AUC remained
unaffected. Plasma concentrations did not differ
following evening or morning drug administration
and reductions in LDL were observed whether or
not rosuvastatin was given with or without food
and regardless of the time of day it was given.
The mean steady state volume of distribu-
tion is 134 liters, with approximately 88% of rosu-
vastatin bound to plasma proteins, mainly albumin.
Metabolism occurs through the cytochrome P450
isozyme 2C9. However, rosuvastatin is not exten-
sively metabolized with only 10% of the radio-
labeled dose recovered as its N-desmethyl metabo-
lite. Following administration, rosuvastatin and its
metabolites are primarily excreted in the feces
(90%), with a half-life of about 19 hours.
A population pharmacokinetics analysis re-
vealed no clinically relevant differences among
Caucasian, Hispanic, and African Americans or Af-
rican Caribbean groups. However, there was a 2-
fold increase in the AUC in Japanese subjects liv-
ing in Japan and in Chinese subjects living in Sin-
gapore when compared to Caucasians living in
North America and Europe. No studies were done
on Asians living in United States.

Precautions and Drug Interactions
Rosuvastatin, like other HMG-CoA reduc-
tase inhibitors, is absolutely contraindicated in
women who are or may become pregnant, as it is a
pregnancy category X drug. There are no pharma-

cokinetic differences due to gender or age. How-
ever, caution is advised in the elderly and those
with renal insufficiency. Plasma concentrations of
rosuvastatin increased 3-fold in patients with severe
renal impairment (CrCl <30 mL/min) compared to
healthy adults with normal renal function (CrCl
>80 mL/min). Mild to moderate renal impairment
(CrCl 30-80 mL/min) had no influence on plasma
concentration when oral doses of rosuvastatin 20
mg were given for 14 days.
Because rosuvastatin's clearance is not de-
pendent on cytochrome P450 3A4 metabolism, 3A4
inhibitors including ketoconazole and erythromycin
are not expected to affect its metabolism.5-6 How-
ever, since it is a substrate for cytochrome P450
2C9, there is a potential for interactions with other
drugs that are also metabolized through this
isozyme, including warfarin. Coadministration of
rosuvastatin and warfarin did not change the war-
farin plasma concentration but it resulted in signifi-
cant increases in the INR (> 4 vs. baseline 2-3).3
The INR should be monitored at baseline and fre-
quently after initiating rosuvastatin.
Coadministration of rosuvastatin 80 mg and
gemfibrozil resulted in a 2.2- and 1.9-fold increase
in the AUC and Cmax of rosuvastatin, respectively.3
However, plasma concentrations of rosuvastatin did
not significantly change when the 10-mg dose was
used. If rosuvastatin is used concurrently with gem-
fibrozil, a lower maximum dosage of 10 mg/day of
rosuvastatin is recommended. Coadministration
with cyclosporine resulted in a 11- and 7-fold in-
crease in the Cmax and AUC of rosuvastatin respec-
tively. It is advisable to avoid concurrent use of ro-
suvastatin and cyclosporine. However, if a station
must be used concurrently with cyclosporine, con-
sider an alternative HMG-CoA reductase inhibitor

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Table 2. Percent change in LDL-C from baseline to week 6 with available stations8
Daily Dose (mg)
Treatment Group Daiy D e
10" 20* 40* 80*
Rosuvastatin -46 -52 -55 ---
Atorvastatin -37 -43 -48 -51
Pravastatin -20 -24 -30 ---
Simvastatin -28 -28 -35 -46
LDL-C low density lipoprotein cholesterol
Values are the percent change from baseline at week 6 expressed as least-squares mean.

that is not metabolized by the CYP450 system or
use lower initial and maximum recommended dos-
ages of rosuvastatin.

Clinical Trials

Dose-Ranging Study
In order to determine the dose-response of
rosuvastatin, Olsson and colleagues7 conducted a 2-
phase, placebo-controlled, multicenter study in pa-
tients with mild to moderate hypercholesterolemia.
The first phase randomized 142 patients to receive
placebo or rosuvastatin at doses of 1, 2.5, 5, 10, 20,
or 40 mg for 6 weeks. The second phase extended
this dosage range and randomized 64 patients to
placebo or rosuvastatin 40 or 80 mg for 6 weeks.
Over the 6-week period, rosuvastatin was well-
tolerated and produced clinically and statistically
significant dose-dependent reductions in LDL-C. It
also produced elevations in HDL-C and reductions
in TG that were statistically significant at some
dose levels. (Table 1)

The Statin Therapies for Elevated Lipid
Levels compared Across doses to Rosuvastatin
(STELLAR) trial was a multi-center, open-label,
parallel group, dose ranging study of rosuvastatin in
12,569 patients with hypercholesterolemia. Rosu-
vastatin 10-80 mg was given as a single daily dose
and total cholesterol, LDL, HDL, and TG were
measured at baseline and after 6 weeks of treat-
ment. Overall, rosuvastatin 10 mg lowered LDL
cholesterol by up to 52% and by as much as 63%
when given at the 40 mg dose. In patients with hy-
pertriglyceridemia, rosuvastatin produced mean re-
ductions from baseline in TG ranging from -10%
to -28% (p<0.001).8

The STELLAR study also compared rosu-
vastatin to the HMG-CoA reductase inhibitors ator-
vastatin, simvastatin, and pravastatin. Rosuvastatin
was able to achieve larger reductions in LDL com-
pared to the other stations, with the 10-mg dose be-
ing roughly equivalent to simvastatin 80 mg and
atorvastatin 40 mg (Table 2). Rosuvastatin was also
superior in reducing TG and increasing HDL com-
pared to the other stations. A 10mg dose reduced TG
by 20% compared to 18% with atorvastatin 10 mg,
12% with simvastatin 20 mg, and 12% with pravas-
tatin 20 mg (p<0.01). Meanwhile, rosuvastatin 10-
40 mg increased HDL cholesterol by 7.7% to 9.6%
compared to 5.2% to 6.8% with simvastatin 10-80
mg, 3.2% to 5.6% with pravastatin 10-40 mg, and
2.1% to 5.7% with atorvastatin 10-80 mg.8

Rosuvastatin vs. Atorvastatin
In a 52-week, randomized, double blind,
multicenter trial, Olsson and colleagues9 compared
the ability of rosuvastatin and atorvastatin to
achieve LDL-C goals in 412 patients with primary
hypercholesterolemia. Patient with LDL-C values
between 160 and 250 mg/dL were randomized to
receive atorvastatin 10 mg or rosuvastatin 5 or 10
mg for 12 weeks followed by 40 weeks in which
dosages could be sequentially doubled up to 80 mg
if National Cholesterol Education Program (NCEP)
Adult Treatment Panel II (ATP-II) LDL-C goals
were not achieved. At 12 weeks, LDL cholesterol
goals were achieved in 76% of patients receiving
rosuvastatin 10 mg versus 53% of patients receiv-
ing atorvastatin 10 mg (p<0.001). Furthermore, in
the subgroup of patients with the most stringent
LDL cholesterol goal of <100 mg/dL, 60% of rosu-
vastatin-treated patients (10 mg) versus 19% of the
atorvastatin-treated patients (10 mg) achieved their
desired LDL-C goal (p<0.001).9

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Table 3. Percent change in lipid measures from baseline at 24 weeks10
Rosuvastatin 40 mg + Rosuvastatin 10 mg +
Lipid Measure Rosuvastatin 40 mg ER Niacin 2 g ER Niacin 1 g ER Niacin 2 g
LDL-C -48t -0.1t -42 -36
Total-C -41 -7t -38 -29t
TG -42 -26 -46 -41
HDL-C 11 12 17 24t
ER extended-release, LDL-C low density lipoprotein cholesterol, Total-C total cholesterol, TG triglycerides, HDL-C high density lipoprotein cholesterol.
* Percent change from baseline is expressed as least-squares mean.
p<0.001; Tp<0.01 (all treatment comparisons vs. rosuvastatin 40 mg).

Rosuvastatin and Niacin
Capuzzi and colleagues1 assessed the
safety and efficacy of rosuvastatin and extended-
release (ER) niacin alone and in combination in
270 patients with total cholesterol values =200 mg/
dL, TG 200 to 800 mg/dL, and HDL<45 mg/dL.
This 24-week, multicenter, open-label trial random-
ized patients to 1 of 4 treatment groups: rosuvas-
tatin 10 to 40 mg, ER niacin 0.5 to 2 g, rosuvastatin
40 mg/ER niacin 0.5 to 1 g, or rosuvastatin 10 mg/
ER niacin 0.5 to 2 g.
Rosuvastatin monotherapy produced the
greatest decrease in LDL-C (-48%) and total cho-
lesterol (-41%) at 24 weeks. Extended-release nia-
cin 2 g alone did not significantly reduce LDL-C
from baseline (-0.1%) and addition of ER niacin 1
g to rosuvastatin 40 mg did not lower LDL-C to a
greater degree than rosuvastatin monotherapy
(Table 3). The lack of effect of niacin can in part be
explained by the significantly higher incidence of
withdrawals and decreases in adherence to treat-
ment seen in the niacin groups that were attributed
to niacin's less favorable side effect profile.

The recommended initial rosuvastatin dose
is 10 mg by mouth once daily. However, 5 mg once
daily should be used for patients who do not require
aggressive LDL-C reductions, patients with renal
insufficiency (CrCl <30 ml/min), or patients at a
high risk for myopathy. The 20 mg dose is recom-
mended for patients with marked hypercholes-
terolemia who require aggressive lipid lowering
therapy (LDL-C >190 mg/dL), while the 40 mg
dose should be reserved for those patients who
have not achieved their LDL-C goal despite being
on the 20-mg dose.3

Toxicity and Safety
The safety profile of rosuvastatin through-
out the dose range of 10 to 40 mg was reviewed in
12,569 patients with hypercholesterolemia.11 The
adverse event profile is similar to that of atorvas-
tatin, simvastatin, and pravastatin and includes
myalgia, asthenia, nausea, and abdominal pain
(Table 4). Elevation of hepatic enzymes >3 times
the upper limit of normal on 2 or more consecutive
occasions occurred in <0.5% of patients. Neverthe-
less, the manufacturer recommends that practitio-
ners check liver function tests (LFTs) at baseline,
12 weeks, and semiannually thereafter.3
Myopathy defined as muscle symptoms of
pain and tenderness plus serum creatine phos-
phokinase (CPK) levels >10 times the upper limit
of normal occurred in =0.03% of patients. How-
ever, it is advisable to check a CPK level at base-
line and at any time symptoms of myopathy de-
velop. There were 7 reported cases of rhabdo-
myolysis in clinical trials; however, these occurred
in patients receiving higher than recommended
doses (i.e. 80 mg) of rosuvastatin. No cases of rhab-
domyolysis or death have been reported with the 40
mg dose to date. Factors that may predispose pa-
tients to myopathy include advanced age (=65
years), hypothyroidism, and renal insufficiency.
In clinical trials, 2 patients taking rosuvas-
tatin 80 mg/day developed acute renal failure of un-
certain etiology; however, they recovered after dis-
continuation of the medication. Dipstick-positive
proteinuria and microscopic hematuria were ob-
served in 6.1%, 1.3%, 0.3%, and 0.3% of patients
receiving 80, 40, 20, and 10 mg of rosuvastatin re-
spectively. Despite the recommendations from an
FDA Advisory Committee for periodic monitoring
of renal function when the 40-mg dose is used, the

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Table 4. Adverse events in placebo-controlled studies3
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 % 1.6 %
Urinary tract infection 2.3 % 1.6 %
Rhinitis 2.2 % 2.1%
Sinusitis 2.0 % 1.8 %

final labeling only provides a precaution to reduce
rosuvastatin dosage in patients receiving the 40 mg/
day dosage who have unexplained persistent pro-
teinuria during routine urinalysis testing.

The mean retail cost for a 30-day supply of
rosuvastatin 5, 10, 20, and 40 mg is $84.64.

Rosuvastatin is the newest HMG CoA re-
ductase inhibitor to be approved by the FDA. Al-
though it has the same mechanism of action as the
other agents in the station class, there are some dif-
ferences in its pharmacokinetic profile. At equiva-
lent doses, rosuvastatin is slightly superior than the
other available stations in decreasing TG and in-
creasing HDL. Rosuvastatin is the only station to be
significantly cleared really; therefore, it should be
used with caution in patients with renal insuffi-
ciency (CrCl <30 ml/min) such as the elderly and
people with diabetes. Outcome data that will
evaluate rosuvastatin's effect on cardiovascular
events and overall mortality are not available how-
ever studies are under way.

1. Third Report of the National Cholesterol Education Pro-
gram (NCEP) Expert Panel on Detection, Evaluation, and
Treatment of High Cholesterol in Adults (Adult Treat-
ment Panel III). Final Report. NIH Publication NO. 02-
5215. 2002. P. VI-9

2. Dipiro JT et al. Pharmacotherapy: A Pathophysiological
Approach, 4th ed.; Appleton and Lange; 1999.
3. Rosuvastatin [Package Insert]. Wilmington, DE: Astra-
Zeneca Pharmaceuticals; 2003.
4. Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly
effective new HMG-CoA reductase inhibitor. Cardiovasc
Drug Rev. 2002 Winter;20(4):303-28.
5. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A,
Schneck DW.The effect of erythromycin on the pharma-
cokinetics of rosuvastatin. Eur J Clin Pharmacol 2003
6. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A,
Schneck DW. Lack of effect of ketoconazole on the phar-
macokinetics of rosuvastatin in healthy subjects. Br J
Clin Pharmacol 2003 Jan;55(1):94-9.
7. Olsson Ag, Pears J, et al. Effect of Rosuvastatin on Low-
Density Lipoprotein Cholesterol in Patients With Hyper-
cholesterolemia. AM J Cardiol 2001;88:504-8.
8. Jones PH et al. Comparison of the efficacy and safety of
rosuvastatin versus atorvastatin, simvastatin, and pravas-
tatin across doses (STELLAR Trial) AM J Cardiology.
2003 Jul 15:92(2): 152-60.
9. Olsson AG et al. Effects of rosuvastatin and atorvastatin
compared over 52 weeks of treatment in patients with
hypercholesterolemia. Am Heart J. 2002 Dec; 144(6):
10. Capuzzi DM, Morgan JM, Weiss RJ, Chitra RR, et al.
Beneficial effects of rosuvastatin alone and in combina-
tion with extended-release niacin in patients with a com-
bined hyperlipidemia and low high-density lipoprotein
cholesterol levels. Am J Cardiology 2003 Jul: 91(11):
11. Brewer HB Jr. Benefit risk assessment of Rosuvastatin
10 to 40 mg. Am J. Cardiology. 2003 Aug 21:92(4B):

AloxiM (palonosetron HC1) is a new 5-HT3
receptor antagonist for the prevention of
acute and delayed nausea and vomiting
associated with initial and repeat courses of
moderately and highly emetogenic cancer
chemotherapy. It is given as a 0.25 mg IV
single dose 30 minutes before the start of
chemotherapy. It is not recommended to
repeat dosing within a 7-day interval and
practitioners should use it with caution in
patients who are at risk for QT prolongation
or on medications that may prolog the QT

Pha rma Note Volume 19, Issue 1 October 2003


Volume 19, Issue 1 October 2003


Issue (Page)

Diagnosis and Management



Role of Proton Pump Inhibitors
Irritable Bowel Syndrome:
Role of Serotonin Modulators
JNC 7 Hypertension Guidelines

Leukotriene Receptor Antagonists:
Role in Allergic Rhinitis
Lyme Disease:
Treatment and Prevention

May '03 (01)
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Index for Volume 18
October 2002 September 2003

May '03 (05)

Nov. '02 (05)

Proton Pump Inhibitors:
Role in the Treatment of GERD

Serotonin Modulators:
Role in the Treatment of IBS


Vardenafil (Levitra) is a new PDE type 5
inhibitor approved for the treatment of
erectile dysfunction. The recommended
starting dose is 10 mg by mouth 60 minutes
before sexual activity, with a maximum
recommended dose of 20 mg. The dose
should be lowered to 2.5 or 5 mg in the
elderly and in patients who are taking CYP
3A4 inhibitors like ritonavir, ketoconazole,
indinavir, itraconazole, and erythromycin.

The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor

Pha rma Note Volume 19, Issue 1 October 2003

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