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CRESTOR TM (rosuvastatin) Clinical Overview

CRESTOR TM (rosuvastatin) Clinical Overview. CRESTOR and GALAXY Programme are trade marks of the AstraZeneca group of companies Licensed from Shionogi & Co. Ltd, Osaka, Japan. Contents. Disease Area Background Rosuvastatin Clinical Development Programme Efficacy Safety and Tolerability

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CRESTOR TM (rosuvastatin) Clinical Overview

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  1. CRESTORTM (rosuvastatin)Clinical Overview CRESTOR and GALAXY Programme are trade marks of the AstraZeneca group of companies Licensed from Shionogi & Co. Ltd, Osaka, Japan

  2. Contents • Disease Area Background • Rosuvastatin Clinical Development Programme • Efficacy • Safety and Tolerability • Clinical Pharmacology • Rosuvastatin Dosing and Administration • Rosuvastatin Ongoing Clinical Development

  3. Disease Area Background

  4. Benefit of Lowering Cholesterol Meta-analysis of 38 primary and secondary prevention trials, with more than 98,000 patients in total 0.0 –0.2 Total mortality, p=0.04 Mortalitylog oddsratio –0.4 Mortality in CHD, p=0.012 –0.6 –0.8 –1.0 0 4 8 12 16 20 24 28 32 Cholesterol reduction (%) Adapted from Gould AL et al. Circulation 1998;97:946–952

  5. On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials – Lower is Better 30 4S-placebo 2° prevention 25 4S-Rx 20 CHD + revasc + stroke CHD Eventrate(%) LIPID-placebo 15 LIPID-Rx CARE-placebo CARE-Rx 10 HPS-placebo 1° prevention HPS-Rx AFCAPS-placebo WOSCOPS-placebo 5 AFCAPS-Rx WOSCOPS-Rx ASCOT-placebo ASCOT-Rx 0 80 100 120 140 160 180 200 Mean on-treatment LDL-C level at follow-up (mg/dL) Rx=treatment Adapted from Ballantyne CM. Am J Cardiol 1998;82:3Q–12Q

  6. 30 Pravastatin 40mg Median LDL-C reduction 10% LDL-C achieved 95 mg/dL Event rate 26.3% 25 16% RR (p = 0.005) 20 Atorvastatin 80mg Median LDL-C reduction 42% LDL-C achieved 62 mg/dL Event rate 22.4% Event rate (%) 15 10 5 0 0 30 3 6 9 12 15 18 21 24 27 Months of Follow-up More Effective LDL-C Lowering Improves Patient Outcomes All-cause death or major cardiovascular events in all randomised subjects Adapted from Cannon C et al. N Engl J Med 2004;350:1495-1504

  7. Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% increasein HDL-C reduces CHD risk by3% 1% decreasein LDL-C reduces CHD risk by1% Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

  8. Many Patients in Need of Lipid Lowering Therapy Remain Untreated – EUROASPIRE II 39% untreated Lipid management assessed in 5556 patients with CHD at least 6 months after discharge who qualify for treatment EUROASPIRE II. Eur Heart J 2001;22:554–572

  9. Many Patients that are Treated are Still not Getting to Goal 2829 patients† 1464 (52%) not at goal on starting dose 1365 (48%) at goal on starting dose 813 (55%) not titrated 651 (45%) titrated 448 (69%)not at goal 203 (31%) at goal †Patients with and LDL-C goal of <100mg/dL (CHD and/or diabetes mellitus) with HDL-C ≤45 mg/dL Foley KA, Simpson RJ, Crouse JR et al. Am J Cardiol 2003;92:79-81

  10. 80 Atorvastatin 10–80 mg Simvastatin 10–40 mg Lovastatin 20–80 mg 60 Fluvastatin 20–80 mg Pravastatin 10–40 mg Patientsat LDL-C goal (%) 40 20 0 Even With Dose Titration, Many Patients Fail to Achieve LDL-C Goals The ACCESS Study At week 54, n=2543 CHD patients Ballantyne CM et al. Am J Cardiol 2001;88:265–269

  11. Evolution of Lipid Management Guidelines – Driving the Need for More Effective Statin Therapy European 2003 European 1994 European 1998 Lower LDL-C goals; wider target population; need for more effective therapies. ATP II 1993 ATP III 2001 ATP I 1988

  12. Rosuvastatin: Addressing The Unmet Medical Need in the Treatment of Dyslipidaemia • A need exists for more efficacious therapy to achieve: • greater LDL-C reductions at low dose • greater LDL-C reductions across the dose range • more patients to guideline LDL-C goals • improved HDL-C raising

  13. RosuvastatinEfficacy

  14. Rosuvastatin dose (mg) Change in LDL-C from baseline (%) Placebo 10 20 40 n=13 n=17 n=17 n=18 0 –10 –7 –20 –30 –40 –50 –52 * –55 * –60 –63 * –70 Rosuvastatin reduces LDL-C by up to 63% *p<0.001 vs placebo Adapted from Olsson A. Cardiovasc Drug Rev 2002;20:303–328

  15. 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;92:152–160

  16. 10 mg 20 mg 40 mg 80 mg STELLAR - Pair-wise Comparisons 10 mg 20 mg 40 mg Rosuvastatin Atorvastatin 10 mg 20 mg 40 mg 80 mg 10 mg 20 mg 40 mg Rosuvastatin Simvastatin 10 mg 20 mg 40 mg Rosuvastatin 40 mg Pravastatin 10 mg 20 mg Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

  17. Dose, mg (log scale) 40 10 20 80 Change in LDL-C from baseline (%) 0 –10 X –20 X –30 n=485 X –40 X n=648 X –50 * n=634 n=473 † ‡ –60 Rosuvastatin versus Comparators:LDL-C Efficacy Across the Dose RangeThe STELLAR Study 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 Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

  18. Change in LDL-C from baseline (%) 0 –5 –10 –15 –20 –25 –30 –35 –40 –45 –50 –55 –60 20 mg † 40 mg ‡ 10 mg * 10 mg 20 mg 40 mg 80 mg Rosuvastatin Atorvastatin Simvastatin 10 mg 20 mg 40 mg 80 mg Pravastatin 40 mg 10 mg 20 mg Rosuvastatin 10 mg (–46%) Rosuvastatin versus Comparators: LDL-C Efficacy at Low DoseThe STELLAR Study *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

  19. 12 weeks 12 weeks 6 weeks 6 weeks 8 weeks 8 weeks Pooled data Pooled data STELLAR STELLAR MERCURY I MERCURY I Change in LDL-C from baseline (%) Jones Schuster Davidson Schwartz Olsson Blasetto 0 n=129 n=128 n=129 n=128 n=127 n=127 n=127 n=127 n=132 n=132 n=139 n=139 n=389 n=389 n=393 n=393 n=158 n=158 n=539 n=539 n=529 n=529 n=529 n=529 n=156 –10 –20 –30 –35 –35 –36 –37 –37 –39 –40 –43 –46 –47 –47 –47 * –50 * * –50 * * * –60 Rosuvastatin 10 mg Atorvastatin 10 mg Rosuvastatin versus Atorvastatin Consistent 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 Cardiol2002;89:268–75 Schwartz G et al. Am Heart J 2004: In Press Olsson AG et al. Am Heart J 2002;144:1044–51 Blasetto JW et al. Am J Cardiol 2003;91(Suppl):3C–10C

  20. Rosuvastatin 10 mg versus Atorvastatin 20 mg Provides Greater LDL-C Reductions 6 weeks 8 weeks MERCURY I Schuster STELLAR Jones Jukema Franken Change in LDL-C from baseline (%) 0 n=156 n=155 n=230 n=231 n=128 n=131 n=539 n=925 -10 -20 -30 -38 -41 -40 -43 -44 -44 -46 -46 -47 * ns * -50 ** Rosuvastatin 10 mg Atorvastatin 20 mg -60 *p<0.05, **p<0.001 vs atorvastatin 20 mg 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.

  21. Rosuvastatin versus Atorvastatin Achievement of LDL-C Goals at Low Dose 100% Rosuvastatin 10 mg # Atorvastatin 10 mg 80% Atorvastatin 20 mg * 77% 67% 66% 60% * 57% European LDL-C goal (%) Patients achieving 2003 52% 40% 36% 20% 13% n=538 n=529 n=925 n=389 n=393 n=201 n=196 0% All patients All patients Patients with CVD or type 2 diabetes 8 weeks MERCURY I Schuster1 12 weeks Pooled data Kritharides2 Rosuvastatin 10 mg vs atorvastatin 10 and 20 mg; patients achieving 2003 European LDL-C goals‡ ‡LDL-C <3mmol/l (115mg/dl) in general;<2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes #p<0.001 vs atorvastatin 10 mg & 20 mg *p<0.001 vs atorvastatin 10 mg 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

  22. Rosuvastatin vs Simvastatin and PravastatinAchievement of LDL-C Goals at Low Dose European LDL-C goal (%) Patients achieving 2003 Rosuvastatin 10 mg vs simvastatin 20 mg and pravastatin 20 & 40 mg; patients achieving 2003 European LDL-C goals‡ 100% Rosuvastatin Simvastatin # * 80% Pravastatin 77% 74% * 60% 55% 49% 40% 38% 37% 20% 12% 10mg 20mg 10mg 20mg 40mg 11% 3% 20mg 10mg 20mg n=74 n=538 n=543 n=521 n=226 n=249 n=252 n=64 n=86 0% 20mg All patients All patients Patients with CVD or type 2 diabetes 8 weeks MERCURY I Schuster1 12 weeks Pooled data Kritharides2 ‡LDL-C <3mmol/l (115mg/dl) in general;<2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes #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

  23. Rosuvastatin versus other statinsAchievement of LDL-C Goals Across Dose Range 100% † # 87% Atorvastatin 83% Simvastatin 80% * 75% Pravastatin 72% 69% 66% 60% 58% European LDL-C goal (%) Patients achieving 2003 48% 44% 40% 36% n=925 n=189 22% 20% 20% 12% 3% 0% 10 20 40 10 20 40 80 10 20 40 80 10 20 40 Dose (mg) Patients achieving 2003 European LDL-C goals‡ ‡LDL-C <3mmol/l (115mg/dl) in general; <2.5mmol/l (97mg/dl) for patients with clinically established CVD or type 2 diabetes Rosuvastatin *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

  24. * 100 40 mg 90 20 mg 80 mg 80 40 mg 10 mg 20 mg 70 60 Patients achieving LDL-C goals (%) 10 mg 50 96% 82% 87% 40 59% 30 20 10 n=106 n=116 0 Rosuvastatin Atorvastatin Rosuvastatin versus Atorvastatin Achievement of LDL-C Goal Across Dose Range Patients 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

  25. Rosuvastatin versus Atorvastatin Achievement of LDL-C Goal Across Dose Range Patients achieving 2003 European LDL-C goal (<2.5mmmol/l)† 100 * 90% 90 40 mg 18 weeks 83% 80 mg 78% 20 mg 12 weeks 80 78% 77% 40 mg 70% 70 60 Patients achieving 2003 European LDL-C goal by dose (%) 50 6 weeks 10 mg 20 mg 40 30 20 10 n=131 n=132 0 Atorvastatin Rosuvastatin *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

  26. Change in HD-C from baseline (%) Rosuvastatin 12 Atorvastatin † * 10 n=473 ns 8 6 4 n=634 2 0 20 40 80 10 Dose (mg); log scale Rosuvastatin versus Atorvastatin Change in HDL-CThe STELLAR Study *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;92:152–160

  27. Rosuvastatin Atorvastatin † 9.5 ‡ 9.6 Simvastatin 12 * 7.7 Pravastatin 6.8 10 6.0 5.7 5.6 5.3 5.2 4.8 4.4 4.4 8 3.2 6 2.1 4 2 10 20 40 10 20 40 80 10 20 40 80 10 20 40 0 Dose (mg) Rosuvastatin versus Comparators Change in HDL-CTheSTELLAR Study Change in HD-C from baseline (%) *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;92:152–160

  28. 0 10 20 40 10 20 40 80 10 20 40 Change in TG from baseline (%) 10 20 40 80 –5 –7.7 –8.2 –10 –11.9 –13.2 –15 –14.8 –17.6 –18.2 –20 Rosuvastatin –19.8 * –20.0 Atorvastatin –22.6 Simvastatin –25 –23.7 † Pravastatin –26.1 ‡ –26.8 –30 –28.2 Rosuvastatin versus Comparators Change in TriglyceridesThe STELLAR Study Dose (mg) *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;92:152–160

  29. 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

  30. Rosuvastatin Tolerability and Safety Adverse event profile Liver Effects Muscle Effects Renal Effects

  31. 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)

  32. 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):23K–29K

  33. 8 7 6 5 Patients (%) 4 3.2% 2.9% 2.5% 2.5% 3 2 10–80 mg 10–40 mg 10–80 mg 10–40 mg 1 0 atorvastatin rosuvastatin simvastatin pravastatin (n=3074) (n=2899) (n=1457) (n=1278) Rosuvastatin Tolerability and Safety - Withdrawals due to Adverse Events Percentage of patients with an adverse event leading to withdrawal Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

  34. 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 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

  35. Rosuvastatin (10, 20, 40 mg) Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg) 3.0 Lovastatin (20, 40, 80 mg) Occurrence ofALT >3×ULN (%) 2.5 Fluvastatin (20, 40, 80 mg) 2.0 1.5 1.0 0.5 0.0 20 30 40 50 60 70 LDL-C reduction (%) Rosuvastatin Benefit:Risk – Liver Effects ALT >3 × ULN: Frequency by 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

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

  37. Rosuvastatin (10, 20, 40 mg) Atorvastatin (10, 20, 40, 80 mg) 3.0 Simvastatin (40, 80 mg) Occurrence of CK >10×ULN (%) 2.5 Pravastatin (20, 40 mg) Cerivastatin (0.2, 0.3, 0.4, 0.8 mg) 2.0 1.5 1.0 0.5 0.0 20 30 40 50 60 70 LDL-C reduction (%) Rosuvastatin Benefit:Risk - Muscle EffectsCK >10 x ULN: Frequency by LDL-C Reduction Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

  38. Rosuvastatin Tolerability and Safety- Renal Effects

  39. Tubular proteinuria Glomerular proteinuria Normal Blood Blood Blood Glomerulus Tubule Bladder Waste Products High molecular weight proteins (includes large amounts of albumin) Low molecular weight proteins (includes small amounts of albumin) Tolerability and Safety - Renal Effects Types of Proteinuria

  40. 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 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;102:52-60 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

  41. Rosuvastatin Tolerability and Safety - ProteinuriaFrequency of Proteinuria* *dipstick positive proteinuria defined as a shift from no protein or trace at baseline to ≥++ Vidt DG et al. Cardiology 2004;102:52-60

  42. 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

  43. 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 72 n=2107 (40 mg) Placebo 71 71 n=109 (40 mg) n=1432 (20 mg) 70 70 70 69 n=119 (20 mg) 69 n=2909 (10 mg) 68 68 68 Change in GFR (ml/min/1.73m2) n=893 (10 mg) 67 67 67 n=371 (placebo) 66 66 65 64 64 64 64 63 Baseline GFR On-treatment Baseline GFR On-treatment GFR GFR Short-term controlled clinical trials (~8 weeks) Long-term open label treatment (>96 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

  44. 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 5 4 Mean change in GFR (ml/min/1.73m2) 3 2 1 n=590 n=836 n=413 n=537 n=243 n=650 n=356 n=303 n=480 n=832 n=46 n=61 0 >65 M N -ve <65 N Y F Y +ve >60 <60 Age, years Gender Hypertension GFR‡ Type 2 Urine dipstick diabetes protein† ‡ml/min/1.73m2 † negative is ‘none or trace’ positive is >1+ at baseline Vidt DG et al. Cardiology 2004;102:52-60

  45. Rosuvastatin Tolerability and Safety - Renal 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 ≥++

  46. 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 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

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

  48. Clinical Pharmacology of Rosuvastatin

  49. Pharmacokinetic 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.

  50. Rosuvastatin - Limited Drug–Drug 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

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