STELLAR Study (Rosuvastatina)

Rosuvastatin Slide Kit May 2004 [1]

STELLAR - Study DesignSTELLAR - Study Design

6 week, randomised, open-label, parallel-group, fixed-dose treatment

2268 adults with primary hypercholesterolaemia

Randomised to 14 groups

– rosuvastatin 10, 20, 40 mg

– atorvastatin 10, 20, 40 or 80 mg

– simvastatin 10, 20, 40 or 80 mg

– pravastatin 10, 20 or 40 mg

Pair-wise comparisons of the data

Percentage change from baseline in lipids assessed after 6 weeks of treatment

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


STELLAR - Pair-wise ComparisonsSTELLAR - Pair-wise Comparisons

Rosuvastatin

Atorvastatin 80 mg10 mg 20 mg 40 mg

10 mg 20 mg 40 mg

Rosuvastatin

Simvastatin 80 mg10 mg 20 mg 40 mg

10 mg 20 mg 40 mg

Rosuvastatin

Pravastatin 10 mg 20 mg 40 mg

10 mg 20 mg 40 mg



Rosuvastatin Atorvastatin Simvastatin

Pravastatin

*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


*

X

X

X

–60

–50

–40

–30

–20

–10

0

Dose, mg (log scale)10 20 40 80

X

X

n=648

n=473

n=634

n=485

†‡

Ch

an

ge in

LD

L-C

fro

m

baselin

e (

%)

Rosuvastatin versus Comparators:Rosuvastatin versus Comparators:LDL-C Efficacy Across the Dose RangeLDL-C Efficacy Across the Dose Range

The STELLAR StudyThe STELLAR Study


Rosuvastatin versus Comparators: LDL-C Rosuvastatin versus Comparators: LDL-C Efficacy at Low DoseEfficacy at Low Dose

The STELLAR StudyThe STELLAR Study Change in LDL-C from baseline (%)

0 –10 –20 –30 –40 –50 –60

10mg*

–5 –15 –25 –35 –45 –55

20mg†

40mg‡

10mg

20mg

80 mg

10mg

20mg

40mg

80mg

10mg

20mg

40mg Rosuvastatin 10 mg (–46%)

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

40mg

*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



Rosuvastatin versus Atorvastatin Rosuvastatin versus Atorvastatin Consistent LDL-C Reduction at Low DoseConsistent LDL-C Reduction at Low Dose

*p<0.001 vs atorvastatin

Jones PH et al. Am J Cardiol 2003;92:152–160 Schuster H et al. Am Heart J 2004; 147: 705-712 Davidson M et al. Am J Cardiol 2002;89:268–75Schwartz G et al. Am Heart J 2004: In PressOlsson AG et al. Am Heart J 2002;144:1044–51Blasetto JW et al. Am J Cardiol 2003;91(Suppl):3C–10C

n=

15

8

n=

53

9

n=

52

9

n=

12

9

n=

12

7

n=

12

8

n=

12

7

n=

13

2

n=

13

9

n=

38

9

n=

39

3

–47–50

–47

–43–46

–47

–36–39

–35–35–37–37

–60

–50

–40

–30

–20

–10

0Jones Schuster Davidson Schwartz Olsson Blasetto

Rosuvastatin 10 mg

Atorvastatin 10 mg

n=

15

6

n=

15

8

n=

53

9

n=

52

9

n=

12

7

n=

12

8

n=

12

7

n=

13

2

n=

13

9

n=

38

9

n=

39

3

6 weeks

STELLAR

8 weeks

MERCURY I

12 weeks

Pooled data

n=

52

9

n=

12

9

**

*

6 weeks

STELLAR

8 weeks

MERCURY I

12 weeks

Pooled data

n=

52

9

***

Ch

an

ge in

LD

L-C

fro

m

baselin

e (

%)


*p<0.05, **p<0.001 vs atorvastatin 20 mg

Rosuvastatin 10 mg versus Atorvastatin 20 mg Rosuvastatin 10 mg versus Atorvastatin 20 mg Provides Greater LDL-C ReductionsProvides Greater LDL-C Reductions

Jones PH et al. Am J Cardiol 2003;92:152–160.Schuster H et al. Am Heart J 2004;147:705–712. Franken A et al. Atherosclerosis Supplements 2004; 5 (1): 118 Abs M.513.Jukema J et al. Atherosclerosis Supplements 2004; 5 (1): 125 Abs M.542.

Rosuvastatin 10 mg Atorvastatin 20 mg

-50

-40

-30

-20

-10

0

-60

6 weeks

MERCURY ISchuster

STELLARJones

ns

-46-43

**

-47-44

*

-46-41

*

-44

-38

FrankenJukema

8 weeks

n=156 n=155 n=230 n=231 n=128 n=131 n=539 n=925

Ch

an

ge in

LD

L-C

fro

m

baselin

e (

%)


1. Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200 2. Kritharides L. Eur Heart J Suppl 2004; 6(Suppl A): A12-A18

Rosuvastatin versus Atorvastatin Rosuvastatin versus Atorvastatin Achievement of Achievement of LDL-C Goals at Low DoseLDL-C Goals at Low Dose

Rosuvastatin 10 mg vs atorvastatin 10 and 20 mg; patients achieving 2003 European LDL-C goals‡

#p<0.001 vs atorvastatin 10 mg & 20 mg *p<0.001 vs atorvastatin 10 mg

‡LDL-C <3mmol/l (115mg/dl) in general;<2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes

77%

66%

52%57%

36%

13%

67%

0%

20%

40%

60%

80%

100%

All patients All patients Patients with CVD or type 2 diabetes

Rosuvastatin 10 mg

Atorvastatin 10 mg

Atorvastatin 20 mg*

n=538 n=925n=529 n=389 n=393 n=196n=201

*

#

12 weeksPooled dataKritharides2

8 weeksMERCURY ISchuster1

Pati

en

ts a

ch

ievin

g 2

003

Eu

rop

ean

LD

L-C

goal (%

)


1. Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200 2. Kritharides L. Eur Heart J Suppl 2004; 6(Suppl A): A12-A18

Rosuvastatin vs Simvastatin and PravastatinRosuvastatin vs Simvastatin and PravastatinAchievement of Achievement of LDL-C Goals at Low DoseLDL-C Goals at Low Dose

77%74%

55%49%

37%

11%

38%

20mg 3%

0%

20%

40%

60%

80%

100%

All patients All patients Patients with CVD or type 2 diabetes

Pati

en

ts a

ch

ievin

g 2

003

Eu

rop

ean

LD

L-C

goal (%

)

*

n=538n=543 n=226 n=249 n=86n=64

*

#

n=74n=252n=521

#p<0.001 vs simvastatin & pravastatin *p<0.001 vs simvastatin & pravastatin

12 weeksPooled dataKritharides2

8 weeksMERCURY ISchuster1

‡LDL-C <3mmol/l (115mg/dl) in general;<2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes

Rosuvastatin

Simvastatin

Pravastatin

Rosuvastatin 10 mg vs simvastatin 20 mg and pravastatin 20 & 40 mg; patients achieving 2003 European LDL-C goals‡

12%20mg 40mg 20mg10mg

20mg

10mg

10mg

20mg


Rosuvastatin versus other statinsRosuvastatin versus other statinsAchievement of Achievement of LDL-C Goals Across Dose RangeLDL-C Goals Across Dose Range

Patients achieving 2003 European LDL-C goals‡

Kritharides L. Eur Heart J Suppl 2004; 6(Suppl A): A12-A18

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

Rosuvastatin

69%

44%

20%

3%

87%

58%

36%

12%

83%

72%

48%

22%

75%

66%

0%

20%

40%

60%

80%

100%

n=925 n=189

*

†#

Atorvastatin

PravastatinSimvastatin

10 20 40 10 20 40 80 10 20 40 10 20 40 80

Dose (mg)

Pati

en

ts a

ch

ievin

g 2

003

Eu

rop

ean

LD

L-C

goal (%

)

‡LDL-C <3mmol/l (115mg/dl) in general; <2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes


Rosuvastatin versus AtorvastatinRosuvastatin versus Atorvastatin Achievement of LDL-C Goal Achievement of LDL-C Goal Across Dose Across Dose

RangeRangePatients achieving NCEP ATP-II LDL-C goals over 52 weeks

*p=0.006 rosuvastatin 10–40 mg vs atorvastatin 10–80 mg

Olsson AG et al. Am Heart J 2002;144:1044–51 Schuster H. Cardiology 2003;99:126–139

100

0

10

20

30

40

50

60

70

80

90

20 mg

59%

40 mg80 mg

82%

20 mg

40 mg

87%96%

AtorvastatinRosuvastatin

n=106 n=116

10 mg

10 mg

*

Pati

en

ts a

ch

ievin

g

LD

L-C

goals

(%

)


*p=0.05 rosuvastatin 40mg vs atorvastatin 80 mg†patients with type 2 diabetes and dyslipidaemia

Adapted from Franken A, Atherosclerosis Supplements 2004; 5 (1): 118 Abs M.513

0

10

20

30

40

50

60

70

80

90

100

Rosuvastatin Atorvastatin

Pati

en

ts a

ch

ievin

g 2

003

Eu

rop

ean

LD

L-C

goal b

y d

ose

(%)

6 weeks

18 weeks

78%83%

90%

70%77%78%

10 mg

12 weeks

*

n=132n=131

20 mg40 mg

20 mg

40 mg

80 mg

Patients achieving 2003 European LDL-C goal (<2.5mmmol/l)†

Rosuvastatin versus AtorvastatinRosuvastatin versus Atorvastatin Achievement of LDL-C Goal Achievement of LDL-C Goal Across Dose Across Dose

RangeRange


Rosuvastatin versus Atorvastatin Rosuvastatin versus Atorvastatin Change in HDL-C Change in HDL-C


*p<0.002 vs atorvastatin 20, 40 and 80 mg†p<0.002 vs atorvastatin 40 and 80 mg


0

2

4

6

8

10

12

10

AtorvastatinRosuvastatin

20 40 80

ns

* †

n=473

n=634

Dose (mg); log scale

Ch

an

ge in

HD

-C f

rom

b

aselin

e (

%)


Rosuvastatin versus Comparators Rosuvastatin versus Comparators Change in HDL-CChange in HDL-C TheThe STELLAR StudySTELLAR Study

*p<0.002 vs pravastatin 10 mg†p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mgObserved data in ITT population


10 20 40

3.2

4.4

5.6

10 20 40 80 10 20 40 0

2

4

6

8

10

12

5.74.8

4.4

2.1

*7.7

†9.5

‡9.6

10 20 40 80

5.3

6.0

5.2

6.8

Dose (mg)

RosuvastatinAtorvastatin

PravastatinSimvastatin

Ch

an

ge in

HD

-C f

rom

b

aselin

e (

%)


Rosuvastatin versus Comparators Rosuvastatin versus Comparators Change in TriglyceridesChange in Triglycerides


*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


Dose (mg)

–20.0

–22.6

–26.8–28.2

–11.9

–17.6

–14.8

–18.2

10 20 40 80

–23.7

† –26.1

‡

–19.8

*

10 20 40 10 20 40 80

–8.2 –7.7

–13.2

10 20 40

–30

–25

–20

–15

–10

0

–5

RosuvastatinAtorvastatin

PravastatinSimvastatinC

han

ge in

TG

fro

m

baselin

e (

%)


Rosuvastatin Efficacy SummaryRosuvastatin Efficacy Summary

Rosuvastatin is the most effective statin at lowering LDL-C- Rosuvastatin has demonstrated highly effective reductions in LDL-C of

up to 63%

- Rosuvastatin lowers LDL-C significantly more than the same and some higher doses of other currently marketed statins

- Rosuvastatin 10 mg lowers LDL-C significantly more than atorvastatin 10 and 20 mg

Rosuvastatin 10 mg enables significantly more patients to achieve their LDL-C goal than the most commonly prescribed doses of other currently marketed statins, thereby reducing the need to titrate to higher doses

Rosuvastatin produces a significant increase in HDL-C which, unlike atorvastatin, is maintained across the dose range


Rosuvastatin Tolerability Rosuvastatin Tolerability and Safetyand Safety

– Adverse event profile

– Liver Effects

– Muscle Effects

– Renal Effects


Rosuvastatin Clinical Studies Included a Rosuvastatin Clinical Studies Included a Wide Range of PatientsWide Range of Patients

Range of patients reflecting those seen in general medical practice

– 53% male; 47% female (including women of childbearing age)

– no upper age limit (31% ≥65 years)

– 17% with type 2 diabetes

– 52% with hypertension

– 36% with overt cardiovascular disease

– 44% with mild renal impairment (8% moderate renal impairment)


Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - Adverse EventsAdverse Events

Rosuvastatin is generally well tolerated with an adverse event profile similar to currently marketed statins

Most common related adverse events - myalgia, asthenia, abdominal pain, nausea; these are generally mild and transient

Well tolerated regardless of age, sex, ethnicity, presence of co-morbidities or concomitant medications

Similar number of adverse events leading to withdrawal (<3%) as other currently marketed statins

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


Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - Withdrawals due to Adverse EventsWithdrawals due to Adverse Events


Percentage of patients with an adverse event leading to withdrawal

0

2

4

6

8

rosuvastatin simvastatin pravastatin

Patients (%)

1

3

5

7

2.9%2.5% 2.5%

(n=3074) (n=1457) (n=1278)

3.2%

atorvastatin(n=2899)

10–40 mg10–80 mg10–80 mg10–40 mg


Rosuvastatin Tolerability and Safety Rosuvastatin Tolerability and Safety - Liver Effects- Liver Effects

Elevations in liver transaminase levels are an infrequent but recognized complication of treatment with statins

Low incidence of clinically significant increases in serum transaminases* with rosuvastatin 10–40 mg of 0.2% which compares well with that seen with other currently marketed statins1

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 Please refer to local Prescribing Information


Rosuvastatin Benefit:Risk Rosuvastatin Benefit:Risk – Liver Effects– Liver Effects

ALT >3 ALT >3 ×× ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction

Persistent elevation is elevation to >3 x ULN on 2 successive occasions


0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Fluvastatin (20, 40, 80 mg)

Rosuvastatin (10, 20, 40 mg)

Lovastatin (20, 40, 80 mg)

Atorvastatin (10, 20, 40, 80 mg)

Simvastatin (40, 80 mg)

Occu

rren

ce o

fA

LT >

3

×ULN

(%

)


Rosuvastatin Tolerability and Safety Rosuvastatin Tolerability and Safety - Muscle Effects- 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

Frequency of treatment-related myopathy* in clinical trials was <0.1% in patients treated with rosuvastatin up to 40 mg which compares well with that seen with other currently marketed statins1

Frequency of rhabdomyolysis with rosuvastatin is similar to that reported for the other marketed statins2

*defined as CK >10 ULN plus muscle symptoms

1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K2. Data on File Please refer to local Prescribing Information


Rosuvastatin Benefit:RiskRosuvastatin Benefit:Risk - Muscle Effects - Muscle Effects

CK >10 CK >10 xx ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction


Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)

Rosuvastatin (10, 20, 40 mg)

Pravastatin (20, 40 mg)

Atorvastatin (10, 20, 40, 80 mg)

Simvastatin (40, 80 mg)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Occu

rren

ce o

f C

K >

10

×ULN

(%

)


Rosuvastatin Tolerability and Rosuvastatin Tolerability and SafetySafety

- Renal Effects- Renal Effects


Tolerability and Safety - Renal Effects Tolerability and Safety - Renal Effects Types of ProteinuriaTypes of Proteinuria

Glomerulus

Normal Glomerular proteinuria

Tubular proteinuria

Blood Blood Blood

Tubule

Bladder

Waste Products

Low molecular weight proteins (includes small amounts of albumin)

High molecular weight proteins (includes large amounts of albumin)


Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - ProteinuriaProteinuria

During the clinical development programme proteinuria* was observed in a small number of patients receiving all statin therapies studied and placebo1

This observation was thoroughly investigated in rosuvastatin patients. It was found to be usually transient, often resolved on continued treatment and not predictive of acute or progressive renal disease1

Proteinuria observed with rosuvastatin was tubular (reduced reabsorption of normally filtered proteins) in origin1

- Development of this tubular proteinuria is likely to be a consequence of the pharmacological action of rosuvastatin, ie. inhibition of HMG-CoA reductase, in the renal tubular cell2,3

- Highly effective inhibition of HMG-CoA reductase together with a greater degree of renal excretion contribute to this being seen with rosuvastatin

*dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++1. Vidt DG et al. Cardiology 2004;102:52-602. Sidaway J et al. Toxicology Letters 2003;144 (supplement 1):s96 Abs 3533. Verhulst A et al. Presented at American Society of Nephrology Nov 2003Please refer to local Prescribing Information


Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - ProteinuriaProteinuria

Frequency of Proteinuria*Frequency of Proteinuria*

Treatment Dose n Patients (%)

Placebo 330 0.6

Rosuvastatin 10 mg

20 mg

40 mg

1008

872

1850

0.6

0.7

1.2

Atorvastatin 10 mg

20 mg

40 mg

80 mg

628

438

63

342

0.5

0.5

0

0.3

Simvastatin 20 mg

40 mg

80 mg

452

314

325

1.1

0.3

0

Pravastatin 20 mg

40 mg

162

64

0.6

0

Vidt DG et al. Cardiology 2004;102:52-60

*dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++


Rosuvastatin Tolerability and Safety – Rosuvastatin Tolerability and Safety – Maintenance of Renal FunctionMaintenance of Renal Function

• In over 6000 patients receiving rosuvastatin (10-40mg) for up to 3.8 years, renal function† was maintained or tended to improve slightly

• This was evident in all patient groups studied, including those at risk of progressive renal disease such as the elderly, patients with type 2 diabetes, hypertension or with pre-existing renal dysfunction/proteinuria and also in those who developed a positive urine dipstick test during the period of treatment*

*dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++†assessed using derived GFR measurements

Vidt DG et al. Cardiology 2004;102:52-60Please refer to local Prescribing Information


66

6768

7070

71

67

6364

6566

6768

6970

7172

Baseline GFR

On-treatmentGFR

Ch

an

ge in

GFR

(m

l/m

in/1

.73m

2)

Rosuvastatin 10 mgRosuvastatin 20 mgRosuvastatin 40 mgPlacebo

6464

68

64

69

Baseline GFR

On-treatmentGFR

Short-term controlled clinical trials (~8 weeks)

Long-term open label treatment (>96 weeks)

n=2909 (10 mg)

n=371 (placebo)

n=1432 (20 mg)

n=2107 (40 mg)

n=893 (10 mg)

n=119 (20 mg)

n=109 (40 mg)

Rosuvastatin Tolerability and Safety – Rosuvastatin Tolerability and Safety – Maintenance of Renal Function Assessed by Maintenance of Renal Function Assessed by

GFRGFRChange in GFR in patients receiving placebo or rosuvastatin in short-term controlled clinical trials and long-term open-label treatment


p<0.001 for rosuvastatin 10 mg, 20 mg and 40 mg vs baseline for both short and long-term treatment


0

1

2

3

4

5

6

Age, years Gender Hypertension GFR‡ Type 2diabetes

Urine dipstickprotein†

Mean

ch

an

ge in

GFR

(m

l/m

in/1

.73m

2)

<65 >65 M F Y N Y N -ve +ve>60 <60

‡ ml/min/1.73m2

† negative is ‘none or trace’ positive is >1+ at baseline

Rosuvastatin Tolerability and Safety – Rosuvastatin Tolerability and Safety – Maintenance of Renal Function in Maintenance of Renal Function in

Different Patient GroupsDifferent Patient GroupsChange in GFR in patients receiving long-term (>96 weeks) with rosuvastatin 10 mg


n=

650

n=

243

n=

413

n=

480

n=

356

n=

537

n=

590

n=

303

n=

61

n=

832

n=

836

n=

46


Rosuvastatin Tolerability and Safety - Rosuvastatin Tolerability and Safety - Renal Safety SummaryRenal Safety Summary

Rosuvastatin 10–40 mg is well tolerated from the renal perspective

Proteinuria* was seen in a small number of patients receiving all statin therapies studied and placebo

Proteinuria observed with rosuvastatin was thoroughly

evaluated and found to be mostly tubular, usually transient, often resolved on continued treatment and not predictive of acute or progressive renal disease

Renal function was maintained or tended to improve slightly with long-term treatment

*dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++


Rosuvastatin - Overall Tolerability and Rosuvastatin - Overall Tolerability and Safety SummarySafety Summary

Tolerability profile has been well-researched in a large number of patients representing ‘real population’

Overall tolerability profile of rosuvastatin comparable with currently marketed statins

– Well tolerated with a low rate of withdrawals due to adverse events (<3%)

– Adverse events usually mild and transient

Low incidence of myopathy and of clinically significant increases in serum transaminases with rosuvastatin 10–40 mg, comparable with currently marketed statins

Renal function was maintained or tended to improve slightly with long-term treatment

Favourable benefit–risk profile


Rosuvastatin - Experience Since LaunchRosuvastatin - Experience Since Launch

As of end April 2004

Rosuvastatin is approved in over 50 countries

>4 million prescriptions issued

>1.5 million patients treated

Benefit–risk profile is consistent with that seen in the clinical development programme and compares favourably with other currently marketed statins


Clinical Pharmacology of Clinical Pharmacology of RosuvastatinRosuvastatin


Pharmacokinetic Profile of Selected StatinsPharmacokinetic Profile of Selected Statins

*Elimination T1/2 of drug and metabolites, if any.CRESTOR (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003. Atorvastatin Calcium Prescribing Information 2002, Pfizer Inc, NY, NY; Simvastatin Prescribing Information, Merck & Co., Inc., Whitehouse Station, NJ; Pravastatin Prescribing Information 2003, Bristol-Meyers Squibb Company, Princeton, NJ.

Rosuvastatin Atorvastatin Simvastatin Pravastatin

CYP450 3A4 metabolism

No Yes Yes No

Clinically significant metabolites

No Yes Yes No

Plasma clearance Dual renal / hepatic

Primarily hepatic

Dual renal / hepatic

Dual renal / hepatic

Relatively hydrophilic Yes No No Yes

Hepatoselective Yes Yes Yes Yes

Bioavailability (%) 20 14 <5 17

Elimination half-life* (hours)

19 14 1.9 77


Interactions of no clinical significance:– drugs where metabolism involves cytochrome P450 such as fluconazole,

ketoconazole and traconazole

– fenofibrate

– digoxin

Interactions with limited clinical significance:– antacid - 50% rosuvastatin levels

– erythromycin non-significant in rosuvastatin plasma levels

Interactions of clinical significance:– oral contraceptive pill - ethinyl oestradiol and norgestrel levels which may affect

choice of oral contraceptive use

– gemfibrozil – 2x in rosuvastatin plasma levels. Combination not recommended

– cyclosporin – 7x in rosuvastatin plasma levels. Combination contraindicated outside of USA

– warfarin – INR – monitoring of INR required

Rosuvastatin - Limited Drug–Drug InteractionsRosuvastatin - Limited Drug–Drug Interactions

Please refer to local Prescribing Information


Rosuvastatin Pharmacokinetics in Special Rosuvastatin Pharmacokinetics in Special Populations Populations

No clinically relevant PK differences:

– between younger and elderly (age ≥65 years)

– between men and women

– between caucasian, hispanic, and black or afro-caribbean groups

– in patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min/1.73m2)

PK differences which may influence dose selection:

– 2-fold increase in AUC in Japanese in Japan and Chinese in Singapore compared with Caucasians in North America and Europe

– increase in Cmax in moderate/severe hepatic impairment

– 3-fold increase in Cmax in severe renal impairment (CLcr <30 mL/min/1.73m2)



Rosuvastatin Dosing and Rosuvastatin Dosing and AdministrationAdministration


Rosuvastatin - Dosing and AdministrationRosuvastatin - Dosing and Administration

Usual start dose 10 mg

– for all patients (new or switch) as it effectively gets most patients to their LDL-C goal

Dose range 10–40 mg

Maximum LDL-C response within 4 weeks

– significant response within 2 weeks

Once daily, any time of day, with or without food



Ongoing Clinical Development Ongoing Clinical Development of Rosuvastatinof Rosuvastatin


Ongoing Clinical Development - the Ongoing Clinical Development - the Rosuvastatin GALAXY ProgrammeRosuvastatin GALAXY ProgrammeTMTM

The GALAXY ProgrammeTM is a large, comprehensive, long-term and evolving global research initiative sponsored by AstraZeneca investigating cardiovascular risk reduction and patient outcomes with rosuvastatin

It has been designed to build on current thinking to address important unanswered questions in statin research

Includes studies investigating the effects of rosuvastatin on:

– atherogenic lipid profile and inflammatory markers

– atherosclerosis

– outcomes Will provide additional short- and long-term efficacy and safety data for

rosuvastatin Designed to help physicians to improve the management of patients

with hypercholesterolaemia and others with or at risk of cardiovascular disease

Schuster H & Fox J. Expert Opinion in Pharmacotherapy 2004;5:1187-1200


GALAXY GALAXY ProgrammeProgrammeTMTM Studies Studies

AURORACORONAJUPITER

ORIONMETEOR

ASTEROID

STELLARMERCURY IMERCURY II

ORBITALDISCOVERY

COMETSLUNARPLUTO

POLARISPULSARECLIPSE

EXPLORER

GALAXY ProgrammeTM studies with rosuvastatin, investigating:

Atherogenic lipid profile+/- inflammatory markers Atherosclerosis

Reduction in CV morbidity & mortality

Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200


Rosuvastatin has the Largest Number of Rosuvastatin has the Largest Number of Outcomes Studies Ongoing at Launch Outcomes Studies Ongoing at Launch

1. Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200 2. Fellström B et al. Nephrol Dial Transplant 2003;18(Suppl 4):7133. Ridker P. Circulation 2003;108:2292–2297

STUDY Treatment Subjects Outcome

AURORA Rosuvastatin 10 mg

2700 subjects with end-stage renal disease on chronic haemodialysis1, 2

Mortality and major CV events

CORONA Rosuvastatin 10 mg

4950 patients with heart failure (NYHA class II-IV) of ischaemic aetiology receiving standard treatment1

Mortality and CV events

JUPITER Rosuvastatin 20 mg

15,000 subjects with normal LDL-C levels and raised levels of C-reactive protein1, 3

Primary prevention of CV events

GISSI-HF Rosuvastatin 10 mg or n-3 PUFA (fish oil)

7000 patients with symptomatic heart failure of any aetiology already receiving standard treatment

Mortality and morbidity


Rosuvastatin - Overall SummaryRosuvastatin - Overall Summary

Rosuvastatin produces beneficial effects on key lipid parameters at low dose and across the dose range

– rosuvastatin is the most effective statin at lowering LDL-C

– rosuvastatin 10 mg reduces LDL-C more than the same and some higher doses of other currently marketed statins

– more patients to LDL-C goal with rosuvastatin 10 mg than commonly prescribed doses of other currently marketed statins, avoiding the need to titrate to higher doses

– HDL-C increases maintained across the dose range, unlike atorvastatin

Tolerability and safety profile similar to other currently marketed statins

Low potential for significant drug–drug interactions

A comprehensive clinical development programme is ongoing, including a large number of outcomes studies

Documents

STELLAR Study (Rosuvastatina)