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STELLAR - 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;92:152160

Rosuvastatin Slide Kit May 2004 [1]

STELLAR - Pair-wise Comparisons


Rosuvastatin 10 mg 20 mg 40 mg

Atorvastatin Rosuvastatin

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

Simvastatin Rosuvastatin

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

Pravastatin

10 mg 20 mg

40 mg

Adapted from Jones PH et al. Am J Cardiol 2003;92:152160

Rosuvastatin Slide Kit May 2004 [2]

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


The STELLAR Study
10 0 Change in LDL-C from baseline (%) 10 20
X X X

Dose, mg (log scale) 40 20

80 Rosuvastatin Atorvastatin Simvastatin Pravastatin

30
40 50 60

n=485 X

X n=648

*
n=473

n=634

*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;92:152160
Rosuvastatin Slide Kit May 2004 [3]

Rosuvastatin versus Comparators: LDL-C Efficacy at Low Dose


The STELLAR Study
Change in LDL-C from baseline (%)
0 5 10 15 20 25 30 35 40 45 50 55 60

10 mg * 10 mg 20 mg 40 mg

20 mg 80 mg

40 mg

Rosuvastatin Atorvastatin Simvastatin Pravastatin

10 mg

20 mg

40 mg

80 mg

10 mg

20 mg

40 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;92:152160
Rosuvastatin Slide Kit May 2004 [4]

Rosuvastatin versus Atorvastatin Consistent LDL-C Reduction at Low Dose


6 weeks
STELLAR Jones
n=158 n=158 n=156

8 weeks
MERCURY I Schuster
n=539 n=539 n=529

12 weeks Pooled data Davidson Schwartz


n=129 n=129 n=127 n=127 n=128 n=128 n=127 n=127

0
Change in LDL-C from baseline (%)

Olsson
n=132 n=132 n=139 n=139

Blasetto
n=389 n=389 n=393 n=393
36 47

10 20 30

37

37

35

35 39

40 50 60

46

43
47

47

50

*p<0.001 vs atorvastatin
Jones PH et al. Am J Cardiol 2003;92:152160 Schuster H et al. Am Heart J 2004; 147: 705-712 Davidson M et al. Am J Cardiol 2002;89:26875 Schwartz G et al. Am Heart J 2004: In Press Olsson AG et al. Am Heart J 2002;144:104451 Blasetto JW et al. Am J Cardiol 2003;91(Suppl):3C10C

Rosuvastatin 10 mg Atorvastatin 10 mg

Rosuvastatin Slide Kit May 2004 [5]

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


6 weeks STELLAR Jones
n=156 n=155

8 weeks Franken
n=128 n=131

Jukema
n=230 n=231

MERCURY I Schuster
n=539 n=925

-10 Change in LDL-C from baseline (%)

-20

-30
-38 -41 -46 * -47 ** Rosuvastatin 10 mg Atorvastatin 20 mg

-40

-46 ns

-43

-44 *

-44

-50

-60 *p<0.05, **p<0.001 vs atorvastatin 20 mg


Jones PH et al. Am J Cardiol 2003;92:152160. Schuster H et al. Am Heart J 2004;147:705712. 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 Slide Kit May 2004 [6]

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


100% Patients achieving 2003 European LDL-C goal (%)

Rosuvastatin 10 mg vs atorvastatin 10 and 20 mg; patients achieving 2003 European LDL-C goals
# 77%

80% 60%

*
67% 57% 66%

Rosuvastatin 10 mg Atorvastatin 10 mg Atorvastatin 20 mg

*
52%
36%

40% 20%
13%

0%

n=538 n=529 n=925

n=389 n=393

n=201 n=196

All patients
8 weeks MERCURY I Schuster1

All patients

Patients with CVD or type 2 diabetes 12 weeks Pooled data Kritharides2

#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
Rosuvastatin Slide Kit May 2004 [7]

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 Pravastatin Achievement of LDL-C Goals at Low Dose


Rosuvastatin 10 mg vs simvastatin 20 mg and pravastatin 20 & 40 mg; patients achieving 2003 European LDL-C goals
100% Patients achieving 2003 European LDL-C goal (%) Rosuvastatin Simvastatin Pravastatin

80%

#
77%

*
74%

60%
49% 38%

*
55%

40%

37%
12%
20mg 10mg

20%

10mg 20mg

40mg

10mg

20mg

11%
20mg

3%
n=74

0%

n=538 n=543 n=521

n=226 n=249 n=252

n=64 n=86 20mg

All patients 8 weeks MERCURY I Schuster1


LDL-C

All patients Patients with CVD or 12 weeks type 2 diabetes Pooled data Kritharides2 <3mmol/l (115mg/dl) in general; <2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes
Rosuvastatin Slide Kit May 2004 [8]

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

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 other statins Achievement of LDL-C Goals Across Dose Range
Patients achieving 2003 European LDL-C goals
100% Patients achieving 2003 European LDL-C goal (%)
LDL-C

*
69%

87% 83%

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

80%

72%

75% 66%

Rosuvastatin Atorvastatin Simvastatin Pravastatin

60%

58% 48% 44%

40%
n=925

36%
n=189

20%

20%

22% 12% 3%

0%

10 20 40

10 20 40 80

10 20 40 80

10 20 40

Dose (mg)
*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
Kritharides L. Eur Heart J Suppl 2004; 6(Suppl A): A12-A18
Rosuvastatin Slide Kit May 2004 [9]

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


Patients achieving NCEP ATP-II LDL-C goals over 52 weeks
100 90 Patients achieving LDL-C goals (%) 80 70 60 50 40 30

*
40 mg 20 mg 80 mg 40 mg 20 mg

10 mg

10 mg

82%

96%
59%

87%

20
10 0
n=106 n=116

Rosuvastatin

Atorvastatin

*p=0.006 rosuvastatin 1040 mg vs atorvastatin 1080 mg Olsson AG et al. Am Heart J 2002;144:104451 Schuster H. Cardiology 2003;99:126139

Rosuvastatin Slide Kit May 2004 [10]

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


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

100 Patients achieving 2003 European LDL-C goal by dose (%) 90 80 70 90% 83% 78%

*
40 mg 20 mg

18 weeks 12 weeks

80 mg 40 mg

78% 77% 70%

60
50 40 30
10 mg

6 weeks

20 mg

20
10 0
n=131 n=132

Rosuvastatin

Atorvastatin

*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
Rosuvastatin Slide Kit May 2004 [11]

Rosuvastatin versus Atorvastatin Change in HDL-C


The STELLAR Study

12
Change in HD-C from baseline (%)

* ns

n=473

Rosuvastatin Atorvastatin

10 8 6 4 2 0

n=634

10

20

40

80

Dose (mg); log scale


*p<0.002 vs atorvastatin 20, 40 and 80 mg p<0.002 vs atorvastatin 40 and 80 mg
Adapted from Jones PH et al. Am J Cardiol 2003;92:152160
Rosuvastatin Slide Kit May 2004 [12]

Rosuvastatin versus Comparators Change in HDL-C


The STELLAR Study
12 10
Change in HD-C from baseline (%)
9.6 9.5 * 7.7 5.7 4.8 4.4 3.2 2.1 6.0 5.3 5.2 4.4

Rosuvastatin Atorvastatin Simvastatin Pravastatin


6.8

8 6 4 2

5.6

10 20 40

10 20 40 80

10 20 40 80

10 20 40

Dose (mg)
*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 mg Observed data in ITT population
Adapted from Jones PH et al. Am J Cardiol 2003;92:152160
Rosuvastatin Slide Kit May 2004 [13]

Rosuvastatin versus Comparators Change in Triglycerides


The STELLAR Study
Dose (mg) 0 5 Change in TG from baseline (%) 10 15 20 25 30
19.8 11.9 14.8 17.6 18.2 8.2 7.7

10 20 40

10 20 40 80

10 20 40 80

10 20 40

13.2

20.0
22.6

23.7

26.1

26.8 28.2

Rosuvastatin Atorvastatin Simvastatin Pravastatin

*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 Adapted from Jones PH et al. Am J Cardiol 2003;92:152160
Rosuvastatin Slide Kit May 2004 [14]

Rosuvastatin 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 Slide Kit May 2004 [15]

Rosuvastatin Tolerability and Safety


Adverse event profile Liver Effects Muscle Effects Renal Effects

Rosuvastatin Slide Kit May 2004 [16]

Rosuvastatin Clinical Studies Included a Wide 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 Slide Kit May 2004 [17]

Rosuvastatin Tolerability and Safety Adverse 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):23K29K

Rosuvastatin Slide Kit May 2004 [18]

Rosuvastatin Tolerability and Safety Withdrawals due to Adverse Events


Percentage of patients with an adverse event leading to withdrawal
8 7

6
Patients (%) 5 4 3 2 1

2.9%
1040 mg

3.2% 2.5%
1080 mg 1080 mg

2.5%
1040 mg

0
rosuvastatin
(n=3074)

atorvastatin
(n=2899)

simvastatin
(n=1457)

pravastatin
(n=1278)

Brewer HB. Am J Cardiol 2003;92(Suppl):23K29K

Rosuvastatin Slide Kit May 2004 [19]

Rosuvastatin Tolerability and Safety - 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 1040 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):23K29K Please refer to local Prescribing Information

Rosuvastatin Slide Kit May 2004 [20]

ALT >3 ULN: Frequency by LDL-C Reduction


Rosuvastatin (10, 20, 40 mg) Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg) Lovastatin (20, 40, 80 mg) Fluvastatin (20, 40, 80 mg)

Rosuvastatin Benefit:Risk Liver Effects

3.0
Occurrence of ALT >3ULN (%)

2.5 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):23K29K
Rosuvastatin Slide Kit May 2004 [21]

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
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):23K29K 2. Data on File Please refer to local Prescribing Information

Rosuvastatin Slide Kit May 2004 [22]

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


Rosuvastatin (10, 20, 40 mg) Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg) Pravastatin (20, 40 mg) Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)

Rosuvastatin Benefit:Risk - Muscle Effects

Occurrence of CK >10ULN (%)

3.0 2.5 2.0 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):23K29K

Rosuvastatin Slide Kit May 2004 [23]

Rosuvastatin Tolerability and Safety - Renal Effects

Rosuvastatin Slide Kit May 2004 [24]

Tolerability and Safety - Renal Effects


Types of Proteinuria
Glomerular proteinuria
Blood Tubular proteinuria Blood

Normal Blood

Glomerulus

Tubule

Bladder

Waste Products High molecular weight proteins (includes large amounts of albumin) Low molecular weight proteins (includes small amounts of albumin)
Rosuvastatin Slide Kit May 2004 [25]

Rosuvastatin Tolerability and Safety Proteinuria


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 HMGCoA 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;102:52-60 2. Sidaway J et al. Toxicology Letters 2003;144 (supplement 1):s96 Abs 353 3. Verhulst A et al. Presented at American Society of Nephrology Nov 2003 Please refer to local Prescribing Information

Rosuvastatin Slide Kit May 2004 [26]

Rosuvastatin Tolerability and Safety Proteinuria


Frequency of Proteinuria*
Dose
10 mg 20 mg 40 mg Atorvastatin 10 mg 20 mg 40 mg 80 mg Simvastatin 20 mg 40 mg 80 mg Pravastatin 20 mg 40 mg

Treatment
Placebo Rosuvastatin

n
330 1008 872 1850 628 438 63 342 452 314 325 162 64

Patients (%)
0.6 0.6 0.7 1.2 0.5 0.5 0 0.3 1.1 0.3 0 0.6 0

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


Vidt DG et al. Cardiology 2004;102:52-60
Rosuvastatin Slide Kit May 2004 [27]

Rosuvastatin Tolerability and Safety Maintenance 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;102:52-60 Please refer to local Prescribing Information
Rosuvastatin Slide Kit May 2004 [28]

Rosuvastatin Tolerability and Safety Maintenance of Renal Function Assessed by GFR


Change in GFR in patients receiving placebo or rosuvastatin in short-term controlled clinical trials and long-term open-label treatment Rosuvastatin 10 mg Rosuvastatin 20 mg Rosuvastatin 40 mg Placebo
n=109 (40 mg)

Change in GFR (ml/min/1.73m2)

72 71 70 69 68 67 66 65 64 63

70 68 67 66

n=2107 (40 mg) 71 70 n=1432 (20 mg) n=2909 (10 mg)

69 n=119 (20 mg) 68


n=893 (10 mg)

67 n=371

(placebo)

64 Baseline GFR On-treatment GFR Baseline GFR On-treatment GFR

Short-term controlled clinical trials (~8 weeks)


p<0.001 for rosuvastatin 10 mg, 20 mg and 40 mg vs baseline for both short and long-term treatment
Vidt DG et al. Cardiology 2004;102:52-60

Long-term open label treatment (>96 weeks)

Rosuvastatin Slide Kit May 2004 [29]

Rosuvastatin Tolerability and Safety Maintenance of Renal Function in Different Patient Groups
Change in GFR in patients receiving long-term (>96 weeks) with rosuvastatin 10 mg 6 Mean change in GFR (ml/min/1.73m2) 5 4 3 2
n=590
n=413 n=650 n=243 n=356 n=537 n=480 n=303 n=832 n=836

<65 >65 Age, years

n=61

>60 <60 GFR

-ve +ve Urine dipstick protein

Gender

Hypertension

Type 2 diabetes

ml/min/1.73m2 negative is none or trace positive is >1+ at baseline


Vidt DG et al. Cardiology 2004;102:52-60
Rosuvastatin Slide Kit May 2004 [30]

n=46

Rosuvastatin Tolerability and Safety Renal Safety Summary


Rosuvastatin 1040 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 Slide Kit May 2004 [31]

Rosuvastatin - Overall Tolerability and Safety 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 1040 mg, comparable with currently marketed statins Renal function was maintained or tended to improve slightly with long-term treatment

Favourable benefitrisk profile


Rosuvastatin Slide Kit May 2004 [32]

Rosuvastatin - Experience Since Launch

As of end April 2004 Rosuvastatin is approved in over 50 countries >4 million prescriptions issued

>1.5 million patients treated


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

Rosuvastatin Slide Kit May 2004 [33]

Clinical Pharmacology of Rosuvastatin

Rosuvastatin Slide Kit May 2004 [34]

Pharmacokinetic Profile of Selected Statins


Rosuvastatin
CYP450 3A4 metabolism Clinically significant metabolites Plasma clearance Relatively hydrophilic Hepatoselective Bioavailability (%) Elimination half-life* (hours) No No Dual renal / hepatic Yes Yes 20 19

Atorvastatin
Yes Yes Primarily hepatic No Yes 14 14

Simvastatin
Yes Yes Dual renal / hepatic No Yes <5 1.9

Pravastatin
No No Dual renal / hepatic Yes Yes 17 77

*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 Slide Kit May 2004 [35]

Rosuvastatin - Limited DrugDrug Interactions


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

Please refer to local Prescribing Information

Rosuvastatin Slide Kit May 2004 [36]

Rosuvastatin Pharmacokinetics in Special 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)

Please refer to local Prescribing Information

Rosuvastatin Slide Kit May 2004 [37]

Rosuvastatin Dosing and Administration

Rosuvastatin Slide Kit May 2004 [38]

Rosuvastatin - 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 1040 mg Maximum LDL-C response within 4 weeks


significant response within 2 weeks

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

Please refer to local Prescribing Information

Rosuvastatin Slide Kit May 2004 [39]

Ongoing Clinical Development of Rosuvastatin

Rosuvastatin Slide Kit May 2004 [40]

Ongoing Clinical Development - the Rosuvastatin GALAXY ProgrammeTM


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

Rosuvastatin Slide Kit May 2004 [41]

GALAXY ProgrammeTM Studies


GALAXY ProgrammeTM studies with rosuvastatin, investigating:
Atherogenic lipid profile +/- inflammatory markers STELLAR MERCURY I MERCURY II ORBITAL DISCOVERY COMETS LUNAR PLUTO POLARIS PULSAR ECLIPSE EXPLORER Reduction in CV morbidity & mortality AURORA CORONA JUPITER

Atherosclerosis ORION METEOR ASTEROID

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

Rosuvastatin Slide Kit May 2004 [42]

Rosuvastatin has the Largest Number of Outcomes Studies Ongoing at Launch


STUDY AURORA Treatment Rosuvastatin 10 mg Rosuvastatin 10 mg Subjects 2700 subjects with end-stage renal disease on chronic haemodialysis1, 2 4950 patients with heart failure (NYHA class II-IV) of ischaemic aetiology receiving standard treatment1 15,000 subjects with normal LDL-C levels and raised levels of C-reactive protein1, 3 7000 patients with symptomatic heart failure of any aetiology already receiving standard treatment Outcome Mortality and major CV events Mortality and CV events

CORONA

JUPITER

Rosuvastatin 20 mg Rosuvastatin 10 mg or n-3 PUFA (fish oil)

Primary prevention of CV events Mortality and morbidity

GISSI-HF

1. Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200 2. Fellstrm B et al. Nephrol Dial Transplant 2003;18(Suppl 4):713 3. Ridker P. Circulation 2003;108:22922297

Rosuvastatin Slide Kit May 2004 [43]

Rosuvastatin - 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 drugdrug interactions A comprehensive clinical development programme is ongoing, including a large number of outcomes studies

Rosuvastatin Slide Kit May 2004 [44]