New era of

Dyslipidaemia treatment
Roviros (Rosuvastatin)
Nabi Qasim Pharma

Dr Jahanzaib Sheikh
Global Burden of Cardiovascular Disease
According to WHO estimates:
• 16.6 million people die of CVD worldwide
each year
• CVD contributed to approximately one third
of global deaths

In 2001:
• 7.2 million deaths from CHD
• 5.5 million deaths from stroke

Adapted from International Cardiovascular Disease Statistics 2003; American Heart Association
Risk Factors for Cardiovascular Disease

• Modifiable • Non-modifiable
– Smoking – Personal history of CHD
– Dyslipidaemia – Family history of CHD
– Age
• raised LDL cholesterol
– Gender
• low HDL cholesterol
• raised triglycerides
– Raised blood pressure
– Diabetes mellitus
– Obesity
– Dietary factors
– Thrombogenic factors
– Lack of exercise
– Excess alcohol consumption
Levels of Risk Associated with Smoking,
Hypertension and Hypercholesterolaemia
Hypertension
(SBP >195 mmHg)

x3

x4.5 x9
x16

x1.6 x6 x4
Smoking

Serum cholesterol level

(>8.5 mmol/L, 330 mg/dL)

Adapted from Poulter N et al., 1993

 Cholesterol: A Major Risk Factor
• In the USA, 102 million people have elevated
total cholesterol (>200 mg/dL, 5.2 mmol/L)1
• In EUROASPIRE II, 58% of patients with established
CHD had elevated total cholesterol
(≥5 mmol/L, 190 mg/dL)2
• 10% reduction in total cholesterol results in:
– 15% reduction in CHD mortality (P<0.001)
– 11% reduction in total mortality (P<0.001)3

• LDL-C is the primary target to prevent CHD

Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II
Study Group. Eur Heart J 2001;22:554–572; 3. Gould AL et al. Circulation 1998;97:946–952.
Cholesterol: A Major Risk Factor

• In the USA, 102 million people have elevated

total cholesterol (>200 mg/dL, 5.2 mmol/L)1

• In EUROASPIRE II, 58% of patients with
established CHD had elevated total
cholesterol (≥5 mmol/L, 190 mg/dL)2

Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II
Study Group. Eur Heart J 2001;22:554–572; 3. Gould AL et al. Circulation 1998;97:946–952.
 Benefit of Lowering Cholesterol
Meta-analysis of 38 primary and secondary prevention trials, with more
than 98,000 patients in total

–0.0
Total mortality, p=0.04
–0.2

–0.4
Mortality, log
odds ratio
–0.6
Mortality in coronary heart disease, p=0.012

–0.8

–1.0
0 4 8 12 16 20 24 28 32 36
Lowering of cholesterol (%)
Gould AL et al. Circulation 1998;97:946–952
 Relationship Between Changes in
LDL-C and HDL-C Levels and CHD Risk

1% decrease
in LDL-C reduces
CHD risk by 1% increase
1% in HDL-C reduces
CHD risk by
3%

Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001.
http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
 Many Patients in Need of Lipid Lowering
Therapy Remain Untreated –
EUROASPIRE II

39% untreated

Lipid management assessed in 5226 patients with CHD at least 6

months after discharge who qualify for treatment
Euro Heart J 2001;22:554-772
 Many Patients that are Treated
are Still not Getting to Goal
2989 patients†

1575 (53%) not 1414 (47%) at

at goal on goal on starting
starting dose dose

838
737 (47%)
(53%) not
titrated
titrated

478 (65%) 259 (35%)

not at goal at goal

†
Patients with and LDL-C goal of <100mg/dL (CHD and/or diabetes mellitus) with
HDL-C ≤45 mg/dL
Simpson RJ Circulation 2001;104:II–829
National Cholesterol
Education Program

Adult Treatment Panel III

(ATP III) Guidelines
 LDL Cholesterol Levels and
CHD Event Rates in Major Statin Trials
Sample Baseline LDL-C net CHD CHD
Study size (n) LDL change event risk reduction
(mg/dL§§) (mg/dL§§)* rate/year† (%)
4S 4444 190 66 5.2‡ 34
PROSPER 5804 147 39 3.8 19
CARE 4159 140 39 2.6 24
LIPID 9014 150 35 2.6 24
HPS 20536 131 39 2.3 27
ALERT 2102 158 39 2.0 35
LIPS 1677 131 35 1.8 31
AFCAPS 6605 150 39 1.0§ 37
WOSCOPS 6595 193 50 1.5 32
ASCOT-LLA 10305 131 39 0.9 36
CHD events refers to cardiac death or nonfatal MI, unless otherwise indicated.
*Placebo-subtracted change from baseline;
†for placebo treated patients;
‡including silent MI plus resuscitated cardiac arrest;
§including unstable angina.
§§1mmole/L LDL = 38.6 mg/dL
 Relationship between
LDL-C and CV Event Rate
30 - Primary prevention
4S - Pl
- Secondary prevention
25 Rx - Statin therapy
Pl - Placebo
Event rate (%)

20 4S - Rx

LIPID - Pl
15
LIPID - Rx CARE - Pl
PROSPER - Pl
CARE - Rx
PROSPER - Rx HPS - Pl
10
HPS - Rx WOSCOPS - Pl
ALLHAT - Pl
ALLHAT - Rx
5 WOSCOPS - Rx
AFCAPS/TexCAPS - Pl

ASCOT - Rx AFCAPS/TexCAPS ASCOT - Pl

- Rx
0
70 (1.8) 90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4)

LDL-C achieved mg/dL (mmol/L)

Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q–12Q.
 Update to ATP III Guidelines:
Rationale
• Since ATP III completion in 2001, 5 large clinical
outcome trials of statin therapy have been
published
– Heart Protection Study (HPS)
– Prospective Study of Pravastatin in the Elderly at Risk
(PROSPER)
– Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial—Lipid-Lowering Trial (ALLHAT-LLT)
– Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm
(ASCOT-LLA)
– Pravastatin or Atorvastatin Evaluation and Infection Therapy
(PROVE-IT) trial
• ATP III update incorporates information from
these trials

Grundy SM et al. Circulation. 2004;110:227-239.

NCEP ATP III LDL Cholesterol Goals

CHD ≥2 <2
LDL cholesterol level (mg/dL)

160 -

130 - Target
100
mg/dL

100 -
Target
70
mg/dL
70 -

Risk factors

(National Cholesterol Education Program, Adult Treatment Panel III, 2004)

 2004 NCEP-ATP III Guidelines
Initiate TLC
(Therapeutic Consider Drug
Risk Category LDL Goal Lifestyle Therapy
Changes)

High risk: <100 mg/dl

(Option: ≥100 mg/dl
×
≥130 mg/dl
≥ 100 mg/dl
CHD or
CHD Risk Equivalents <70 mg/dl) (<100 mg/dL: consider drug
options)

Moderately high ≥ 130 mg/dl

risk: (100–129 mg/dL:
10-20% risk <130 mg/dl consider drug options)
2+ Risk
(Option: <100 ≥130 mg/dl
Factors
mg/dl)
Moderately risk:
≥160 mg/dl
<10% risk

≥ 190 mg/dl
Lower risk: (160–189 mg/dL:
<160 mg/dl ≥160 mg/dl
0-1 Risk Factor LDL-C–lowering drug
optional)
Cholesterol-Lowering Drug Therapy
Cholestyramine HMG CoA Reductase
 Colestipol
Inhibitors
 Colesevelam
 Lovastatin
Fibrates  Simvastatin
 Gemfibrozil  Pravastatin
 Fenofibrate  Atorvastatin
 Clofibrate  Cerivastatin
(2001/8 withdrawal from market)
Nicotinic Acid
 Rosuvastatin
Ezetimibe  Pitavastatin
 Niacin/Lovastatin
 Amlodipine/Atorvastatin
 Aspirin/Pravastatin
 Cholestyramine
Mechanism of action
Bind bile acids and metabolites of cholesterol in the
intestine through anion exchange
Pharmacodynamics
Moderate reduction in LDL-C levels
- LDL-lowering potential increases when
combined w/ other agents (e.g. statins)
- May raise TG levels in some p’ts
- ↓ LDL-C by 15-30%
- ↑ HDL-C by 3-5%
Adverse effects
GI distress (constipation, bloating) interfere with
absorption of fat-soluble
vitamins triglyceridemia hyperuricemia
 Fibrates
Mechanism of action
As ligands for the nuclear transcription receptor, peroxisome
proliferator-activated receptor-apha (PPAR-α). Increase
lipolysis of lipoprotein triglyceride via LPL.
Pharmacodynamics
Lower TG & raises HDL
- Primarily targets atherogenic dyslipidemia including
diabetic dyslipidemia
- ↓ LDL-C by 5-20% (in non-hypertriglyceridemic individuals)
- ↑ HDL-C by 10-35%; ↓ TG by 20-50%
Adverse effects
GI symptoms, headache, drowsiness, dizziness,
myopathy, gallstone rish , arrhythmias
 Nicotinic Acid
Mechanism
Alter lipid levels by inhibiting lipoprotein synthesis &
decreasing the production of VLDL particles by the liver
Pharmacodynamics
Most effective at raising HDL levels of the lipid-
modifying drugs
- ↓ LDL-C by 5-25%
- ↑ HDL-C by 15-35%
- ↓ TG by 20-50%
Adverse effects
Flushing, itching, rash, GI upset
 Ezetimibe
Mechanism
Inhibit absorption of cholesterol from intestine.
Pharmacodynamics
A decreased delivery of cholesterol to the liver.
Reduction of hepatic cholesterol stores.
An increased clearance of cholesterol from the blood.
- ↓ total LDL-C ↓ LDL-C
- ↓ TG ↓ Apo-B
- ↑ HDL-C
Adverse effects
headache, Chest pain, arthralgia, GI distress
 Statins
Mechanism
Inhibit HMG CoA reductase which is the rate-limiting step
in cholesterol biosynthesis.
Pharmacodynamics
Most effective class of drugs at lowering LDL-C levels
- ↓ LDL-C by 18-55%
- ↑ HDL-C by 5-15%
- ↓ TG by 7-30%
Adverse reactions
myopathy, rhabdomyolysis, elevations of serum
aminotransferase activity
 Mechanism of Action of Statins
Cholesterol Synthesis Pathway
acetyl CoA
HMG-CoA synthase
HMG-CoA
HMG-CoA reductase X Statins
mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

ubiquinones farnesyl pyrophosphate dolichols

Squalene synthase squalene

cholesterol
 Fluvastatin
Atorvastatin Rosuvastatin
Pravastatin
B M Y

1991 1996 2000

1987 1993 1997 2003

Lovastatin
Cerivastatin
Simvastatin
 Why Do We Need a New Statin?

 Only about 50% of patients with high

LDL-C achieve goal on current lipid lowering therapies
– Non-compliance
– Lack of effective treatment
– Fear of high dose titration
 More effective cholesterol-lowering
agents are needed to attain LDL-C goals1,2

1
Kotseva, K, Wood D, de Backer, G et al. 2001
2
Pearson T et al. 2000
Wish List of Features of New Statin
 High efficacy at start dose
Potent HMG-CoA inhibition
Lowers LDL, VLDL, Lp(a), remnants
Raises HDL
Anti-inflammatory, anti-thrombotic
 Good safety profile
Selective for target organ – liver
Minimal potential for drug interactions
 Useful in a wide range of patients
 Cost effective

After Hanefeld, Int J Clin Pract 2001 55;399–405

 Rosuvastatin:
A new hydrophilic statin – single enantiomer
Statin Pharmacophore
Relative lipophilicity *

O Ca 2.0
(3R, 5S) HO cerivastatin
O simvastatin
1.5
OH fluvastatin
1.0 atorvastatin
F
C H3 0.5

C H3 0.0

N N rosuvastatin
-0.5

H 3C N pravastatin
-1.0
S C H3
O O * log D at pH 7.4

Buckett et al., (2000); Mc

 Rosuvastatin: Hepatoselective
Cholesterol synthesis inhibited in hepatocytes at
1000-fold lower concentrations than fibroblasts
Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts

140

120
% of Control Fibroblasts IC50= 331 nM
Mean Hepatocytes IC50= 0.2 nM
100

80

60

40

20

0
0 0.1 1 10 100 1000 10000 100000
Concentration (nM)
Buckett et al., (2000)
 Cerivastatin: Non hepatoselective
Cholesterol synthesis inhibited in fibroblasts
and hepatocytes at similar concentrations
Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts
140

120
% of Control Fibroblasts IC 50= 1.3 nM
Mean Hepatocytes IC
100 50 = 2.4 nM

80

60

40

20

0
0 0.01 0.1 1 10 100 1000 10000 100000
Concentration (nM)
Buckett et al., (2000)
Rosuvastatin: X-Ray crystallography provides
molecular rationale for potent enzyme inhibition

The rosuvastatin:
HMG-CoA reductase
complex has more
bonding interactions
than any other statin

binding interaction
Arg568 and sulphone

Istvan and Deisenhofer (2001)

 Rosuvastatin: Potent inhibitor of
HMG-CoA reductase in human catalytic domain
Three determinations, IC (nM) with 95% confidence limits
50

Rosuva
5.4
Atorva
8.2 Ceriva * Simva *
10.0
11.2
IC50(nM)
(log scale)
10 Fluva ***
27.6
***
Prava
44.1

100
*P<0.05 vs Rosuvastatin; ***P<0.001 vs Rosuvastatin
McTaggart et al., (2001)
 Rosuvastatin:
Well defined pharmacology
Potency on Cell selectivity Hepatic Elimination
enzyme log ratio Metabolism Half Life
IC50 (nM) by Cyt P450 (hours)
3A4

rosuvastatin 5.4 3.3 No ≈19

atorvastatin 8.2 2.2 Yes 14

cerivastatin 10.0 –0.14 Yes 2–3

simvastatin 11.2 0.54 Yes 1–2

fluvastatin 27.6 –0.04 No 1–2

pravastatin 44.1 3.3 No 1–2

Adapted from Davidson., (2002)

Pharmacologic properties of Statins
Property Rosuva Atorva Fluva Lova Prava Simva

Prodrug No No No Yes No Yes

Salt form Ca Ca Na None Na None

Single Yes Yes Yes Yes Yes Yes

isormer

Lipophilicity
-0.3 +4.1 +3.2 +4.3 -0.2 +4.7
(log P)

IC50(nm)
5 8 28 NA NA 11
Potency

Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004)

Pharmacokinetic properties of Statins
Parameter Rosuva Atorva Fluva Lova Prava Simva

Absolute bioavailability,% 20 12 10-35 <5 18 >5

Food effect on bioavailability None ↓13% ↓15-25% ↑50% ↓ 30% None

Protein binding, % 90 >98 >99 95 48 95

Hepatic extraction, % dose 90 >70 68 >70 50 78-87

Metabolic enzyme (none) Sulfation

3A4(S) 2C9(I) 3A4(S) 3A4(S)
2C9,2C19 (none)
(S, substrate; I, inhibitor)

Half-life, h 20 14 <1 3-4 1.8 3

Elimination, %
10 2 5 10 20 13
Urine
90 96 95 70 70 80
Feces

Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004)

 ROVIROS®
Rosuvastatin

is the most effective statin at lowering LDL-C

and produces a significant increase in HDL-C
 GALAXY
GALAXY Programme studies with CRESTOR, investigating:

Atherogenic lipid profile Reduction in CV

+/- inflammatory markers Atherosclerosis
morbidity & mortality
STELLAR ORION (MRI) AURORA
MERCURY I/II METEOR CORONA
ORBITAL ASTEROID (IVUS) JUPITER
DISCOVERY
COMETS
LUNAR
PLUTO
POLARIS
PULSAR
ECLIPSE
EXPLORER
PLANET

FFPC meeting October 2003: Dr Dave Kallend

 Rosuvastatin
the most effective statin at lowering LDL- C
Dose (mg)
10 20 40 80
Log scale
0
LS mean % change from baseline

-10

-20 20.1%

28.3%
-30 29.7%

36.8%
-40
45.8% 45.8%
-50
51.1%
55.0%
-60

CRESTOR atorvastatin simvastatin pravastatin

STELLAR Study. Am J Cardiol 2003; 92: 152–60.

 Statin Dose Required to Achieve
45–50% LDL-C Reduction

10 20 40 80 mg

Rosuva

Atorva

Simva

Not achieved with max.

Prava
authorised dose

Not achieved with max.

Fluva authorised dose

Adapted from Jones P.H. 2003

 Rosuvastatin versus Comparators:
LDL-C efficacy at 10mg Dose
Change in LDL-C from baseline (%)
0 –5 –10 –15 –20 –25 –30 –35 –40 –45 –50 –55 –60

10 20 40
mg mg mg
* † ‡

10 20 40 80
mg mg mg mg
Rosuvastatin
Atorvastatin
10 20 40 80 Simvastatin
mg mg mg mg Pravastatin

10 20 40
mg mg mg Rosuvastatin 10 mg (–46%)

*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg
†p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg
‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160 The STELLAR Study

 Rosuvastatin:
10 mg gets more patients to their LDL-C goal
than the start doses of the most commonly used
statins1,2,3,4 Percentage of patients at LDL-C goal at week 6 1, 2

100%
P-values
***p<0.002
90% CRESTOR 10 mg
% patients reaching LDL-C goal*

vs. atorvastatin
10 mg pravastatin
10, 20 & 49 mg and
80% * simvastatin 10, 20,
80 mg & 40 mg
70%
40 mg
10
10 mg
mg
80 mg
60% Usual
Usual start
start doses
doses
20 mg

50%
40 mg
10 mg
10
10 mg
mg
40%
20
20 mg
mg
30%

20% 40 mg
10 mg
n=160

10% n= n= n= 20mg
20
20 mg
mg
156 158 158
10 mg
CRESTOR atorvastatin simvastatin pravastatin

References: 1. STELLAR 2. Schuster MERCURY I Am Heart J 2004; 147: 705-12. 3.

Krithiades Eur Heart J Suppl 2004; 6(suppl A): A12-A18.4. Shepherd Am J Cardiol
2003; 92(suppl): 11C-19C. *2003 European goals
Rosuvastatin 10 mg gets more patients to
Patients achieving LDL-C goal (%)
NCEP ATP- III LDL-C Goals
100
P<0.01
90 p<0.0001
80 OMNITOR
80 atorvastatin
70 74
60 63
50
40 Baseline mean LDL-C values (mg/dL)
OMNITOR 10 mg: 165.1 (4.28 mmol/L)

30 atorvastatin 10 mg: 162.6 (4.21)

atorvastatin 20 mg: 167.1 (4.33)

20
10
n=535 n=528 n=923
0
10 10 20
Dose (mg/day)
•high risk (with CHD or CHD risk equivalent) - Target LDL-C: <100mg/dL (2.59mmol/L)

MERCURY I study; Am Heart J 2004; 147: 705-12

 Rosuvastatin: 10mg enables more patients with
hypercholesterolemia to reach their Joint European
Societies LDL-C goals, than atorvastatin 10mg
Patients reaching European LDL-C goals by risk category at week 12
(Pooled Data)
100 rosuvastatin 10mg
atorvastatin 10mg
**
Patients achieving goal (%)

*** ***
80 85
81 82

60 64

51
40 49

20

n=75 n=66 n=314 n=327 n=389 n=393

0
10-yr CHD risk < 20% High CHD risk All Categories

Joint European Societies Cholesterol Categories

**P<0.01 vs atorvastatin; ***P<0.001 vs atorvastatin

Shepherd et al., (2003)
 Rosuvastatin 10 mg gets more patients to
European LDL-C Goals

100 *
90 *
88
84 *
80
76
70 69
Patients 62
at goal 60
(%) 50
40
30
20
10
0
R10 A10 A20 S20 P40

*p<0.0001 (R10 vs A10, S20 & P40) 1998 European goal <3.0 mmol/l (116 mg/dl)

MERCURY I study; Am Heart J 2004; 147: 705-12

 Rosuvastatin 10 mg
Patients (%) achieving European LDL-C goal
100 † ‡
* 90 ‡
90 88 86 86 86 88
84
80
80 72
70 66

Patients 60
at goal
50
(%)
40
30
20
10
0
Dose A10
A10 (mg) A20 A20 A20 S20 S20 P40 P40
R10 A10 R10 R20 A20 R10 S20 R10 P40

vs A10/A10;
vs A20/A20;
10 vs S20/S20 and P40/R10 vs P40/P40)
al <3.0 mmol/l (116 mg/dl)
MERCURY I study; Am Heart
 Rosuvastatin effectively raises
HDL-C 1
LS mean % change from baseline

12

10

0
10 20 40 80
Log scale
Dose (mg)
CRESTOR atorvastatin simvastatin pravastatin

STELLAR Study. Am J Cardiol 2003; 92: 152–60.

 Rosuvastatin effectively reduces TG
Dose (mg)
10 20 40 10 20 40 80 10 20 40 80 10 20 40
0

–5
Change in –8.2 –7.7
TG from –10
baseline –11.9
–15 –13.2
(%) –14.8

–17.6 –18.2
–20 –19.8 –20 Rosuvastatin
Atorvastatin
* –23.7 –22.6
–25 Simvastatin
** –26.1 –26.8 Pravastatin
–30 †
–28.2

*p<0.002 vs pravastatin 10, 20 mg

**p<0.002 vs simvastatin 40 mg; pravastatin 20, 40 mg
†p<0.002 vs simvastatin 40 mg; pravastatin 40 mg

Jones PH, et al. Am J Cardiol 2003;92:152–160

Rosuvastatin reduces in Inflammatory Marker
C-Reactive Protein (ANDROMEDA)
8 weeks 16 weeks
RSV ATV RSV ATV
10 mg 10 mg 20 mg 20 mg
0

-5
baseline in hsCRP (%)

-10
Mean change from

-15
-21.2
-20
Rosuvastatin (RSV)
-25 Atorvastatin (ATV)
-30
-34.0 -33.8
-35
-39.8
-40

-45 74th EASC 17-20 April 2004, Seville, Spain

 Pleiotropic Effects of Rosuvastatin
in Animal Models of Vascular Disease

 ↑ eNOS, NO availability
 ↓ leukocyte-endothelial interactions
 ↓ superoxide, oxidative stress
 Preservation of vascular function in
hypertension and insulin-resistance
 Protection against ischaemia-reperfusion
injury
 Protection of kidney function and inhibition
of renal fibrosis and glomerulosclerosis
 Statins – Therapeutic Ratio

Adverse Effects

Therapeutic
Effects i sk
R

efi t
Be n
Muscle
Liver
Cardiovascular
protection Drug interactions
 Rosuvastatin Tolerability and Safety –
Withdrawals due to Adverse Events
10
Percentage of patients with an adverse event
9 leading to withdrawal
Percentage of patients

7
6

5
4
2.9% 3.2%
3 2.5% 2.5%
2
10-80 mg
10-40 mg 10-80 mg 10-40 mg
1
0
rosuvastatin atorvastatin simvastatin pravastatin
(n=3074) (n=2899) (n=1457) (n=1278)

Brewer HB. Am J Cardiol 2003;92(Suppl):23K-29K

 Rosuvastatin Tolerability and Safety
- Muscle Effects
 As with other statins, effects on skeletal muscle, e.g.
uncomplicated myalgia, myopathy and, rarely,
rhabdomyolysis have been reported in patients treated
with rosuvastatin
 Incidence of treatment-related myopathy* in clinical
trials was low in patients treated with rosuvastatin up to
40 mg (<0.1%) which is similar to that seen with other
currently marketed statins1
 Frequency of rhabdomyolysis with rosuvastatin is very
rare (<0.01%) which is in line with that reported for
other marketed statins2

*defined as CK >10 ULN plus muscle symptoms

1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

2. Data on File
Please refer to local Prescribing Information
 Rosuvastatin - Muscle Effects
CK >10 x ULN: Frequency by
LDL-C Reduction
3.0 Rosuvastatin (10–40 mg)
Atorvastatin (10–80 mg)
2.5 Simvastatin (40–80 mg)
CK >10 × ULN (%)

Pravastatin (40–80 mg)

2.0 Cerivastatin (0.2–0.8 mg)

1.5

1.0

0.5

0.0
20 30 40 50 60 70
LDL-C reduction (%)

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

 Reported Cases of Fatal Rhabdomyolysis and
Numbers for All Statins Dispensed in the US Since
These Products Were Launched
Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Cerivasta Rosuvastati
tin n
Variable
*

Date approved 8/87 10/91 12/91 12/93 12/96 6/97 11/02#

Fatal cases of 19 3 14 0 6 31 0
rhabdomyolysis

No. of
prescriptions 99,197 81,364 116,145 37,392 140,360 9,815 10,100
dispensed since
marketing began
(in thousands)

Reporting rate 0.19 0.04 0.12 0 0.04 3.16 0

(per 1 million
prescriptions)

*worldwide prescriptions
#Netherlands (MR ref state)
Adapted from: Steffa JA, et al. N Engl J Med. 2002;346:539-540.
 Rosuvastatin Tolerability and Safety
- Liver Effects
 Elevations in liver transaminase levels are an infrequent
but recognized complication of treatment with statins
 Incidence of clinically significant increases in serum
transaminases* with rosuvastatin 10–40 mg in clinical
trials was low (0.2%) which is similar to that seen with
other currently marketed statins1,2
 As with other statins:
– liver function tests recommended
– caution in patients who consume excessive quantities of
alcohol and/or have a history of liver disease
– contraindicated in patients with active liver disease

*ALT >3 x ULN on 2 successive occasions

1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

2. Shepherd J et al. Am J Cardiol 2004;94:882-888
Please refer to local Prescribing Information
 Rosuvastatin – Liver Effects

Persistent ALT >3 × ULN: Frequency by

LDL-C Reduction Rosuvastatin (10–40 mg)
Atorvastatin (10–80 mg)
3.0 Simvastatin (40–80 mg)
Persistent ALT >3 × ULN (%)

Lovastatin (20–80 mg)

2.5 Fluvastatin (20–80 mg)

2.0

1.5

1.0

0.5

0.0
20 30 40 50 60 70
LDL-C reduction (%)
Persistent elevation is elevation to >3 x ULN on 2 successive occasions

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

 Potential Drug Interactions
3A4 2C9
 Simvastatin • Fluvastatin
• Phenytoin
 Atorvastatin
• Fluconazole
 Lovastatin
• Warfarin
 Diltiazem
• Rosuvastatin
 Clopidogrel
 Amiodarone Low potential for
 Cimetidine cytochrome P450
 Ery/clarithromycin interactions with
rosuvastatin
 Ketoconazole
 Carbamazepine
 St John’s wort
 Grapefruit juice
 Rosuvastatin Safety

Safety profile of rosuvastatin, including

effects on liver enzymes and creatine
kinase, compares favorably to those of
other marketed statins from 10–40 mg
daily in all pre-approval studies
• Hydrophilic properties

• Good selectivity for target organ – liver

• Limited metabolism by cytochrome P450

(2C9‚2C19)
Rosuvastatin: Drug Interactions

Interactions of limited significance:

• Oral contraceptives - ↑ ethinyl oestradiol and norgestrel
• Antacid - ↓ 50% rosuvastatin levels
• Erythromycin - ↓ 20–30% rosuvastatin plasma levels
• Warfarin – transient ↑ INR in some patients

Not recommended for use with:

• Gemfibrozil – 2x increase in rosuvastatin plasma levels
(Note: Fenofibrate may be co-administered)

Contraindication:
• Cyclosporin – 7x increase in rosuvastatin AUC
• ANY fibrate with rosuvastatin 40 mg
Rosuvastatin: Limited drug-drug interactions
 No clinically significant interactions seen or expected with:
• Fluconazole / Ketoconazole / Itracnoazole
• Fenofibrate
• Digoxin
• Drugs mediated by cytochrome P450 metabolism
 Interactions with limited clinical significance:
• Oral contraceptive pill - ↑ ethinyl oestradiol and norgestrel levels
• Antacid - ↓ 50% rosuvastatin levels
• Erythromycin - ↓ 20-30% rosuvastatin plasma levels
• Warfarin – ↑ INR
 Interactions resulting in not recommended for use:
• Gemfibrozil – 2x increase in rosuvastatin plasma levels
 Interactions resulting in contraindication to concomitant use:
• Cyclosporin – 7x increase in rosuvastatin plasma levels
Rosuvastatin Summary of Product Characteristics;
Martin PD et al., (2001); Cooper et al., (2001); Kemp et al., (2001)
Rosuvastatin has Extensive Clinical and
post-Market Experience Mar 2005
• Approved in 73 countries world-wide
• Over 5 million patients treated
• Over 20 million prescriptions written
• Over 45,000 patients have been treated with
Rosuvastatin in our clinical trial programme
---- GALAXY program
 Thanks for

your attention !