CRESTOR ® Safety

1. CRESTOR®Safety Howard G. Hutchinson, MD Vice President, Clinical Research

2. Objectives of the Rosuvastatin Clinical Development Program • Provide an overall benefit-risk profile demonstrating • Greater beneficial effects on key lipid parameters at both the start dose and across the dose-range compared with marketed statins • A similar safety profile compared with approved drugs in the statin class • A low potential for significant drug-drug interactions

3. 9 Safety Overview • Safety data come from 27 clinical trials conducted worldwide • ~ 50% of patients were from the United States • 12,569 patients treated with rosuvastatin at doses up to 80 mg • > 14,000 patient-yr of exposure

4. Safety Presentation Agenda • Demographics • Exposure • Adverse events • Liver effects • Skeletal muscle effects • Renal effects • Drug-drug interactions

5. 9 Demographic Characteristics of Patients (1)Combined All Controlled/Uncontrolled and RTLD Pool PTT C1.4.1 andC1.4.2

6. 9 Demographic Characteristics of Patients (2)Combined All Controlled/Uncontrolled and RTLD Pool PTT C1.4.1 andC1.4.2

7. 9 Baseline Medical Conditions of InterestCombined All Controlled/Uncontrolled and RTLD Pool PTT C1.4.4 andC1.4.6 †Creatinine clearance (CrCI) derived using Cockcroft-Gault formula.

8. 9 Maximum Continuous Duration of TreatmentCombined All Controlled/Uncontrolled and RTLD Pool PTT C2.4.3 and C2.4.4 Total patients – 12,569 Total patient-yr – 14,231

9. Summary of Patient-Reported Adverse Events • The frequency and types of AEs reported were similar to comparator statins • The frequency and types of AEs were similar at the 5-mg, 10-mg, 20-mg, and 40-mg doses • At the 80-mg dose, increased frequencies of nausea, myalgia, asthenia, and constipation were observed • Well tolerated regardless of age, sex, ethnicity, presence of comorbidities, or concomitant medications

10. Safety Presentation Agenda • Demographics • Exposure • Adverse events • Liver effects • Skeletal muscle effects • Renal effects • Drug-drug interactions

11. Evaluation of Rosuvastatin Effects on the Liver • Liver function tests were evaluated at each visit • In this section, the percentage of patients with ALT > 3 × ULN on 2 occasions (“persistent elevations”) is presented • AST changes mirrored ALT changes • ALT increases associated with bilirubin increases were rarely observed

12. Persistent ALT Elevations by DoseCombined All Controlled/Uncontrolled and RTLD Pool

13. Fluvastatin (20 - 80 mg) Lovastatin (20 - 80 mg) Simvastatin (40 - 80 mg) Atorvastatin (10 - 80 mg) Rosuvastatin (5 - 80 mg) Persistent ALT > 3 × ULN Frequency by % LDL-C Reduction Ref: Prescribing Information and Summary Basis of Approval documents.

14. Safety Presentation Agenda • Demographics • Exposure • Adverse events • Liver effects • Skeletal muscle effects • Renal effects • Drug-drug interactions

15. Evaluation of Rosuvastatin Effects on Skeletal Muscle • Creatine kinase (CK) was evaluated at each visit • In this section, the following data are presented • CK > 10 × ULN • Myopathy: CK > 10 × ULN + muscle symptoms • Rhabdomyolysis: myopathy + hospitalization + intravenous fluids

16. 9 CK > 10 × ULN by DoseCombined All Controlled/Uncontrolled and RTLD Pool

17. 9 Cases of MyopathyCombined All Controlled/Uncontrolled and RTLD Pool CK elevations > 10 × ULN plus muscle symptoms.

18. 9 Risk Factors for Myopathy (80-mg Dose) • Age • < 65 yr 0.2% (2/1200) • ≥ 65 yr 2.3% (9/383) • Renal insufficiency • CrCl ≤ 80 mL/min 1.2% (9/760) • CrCl > 80 mL/min 0.2% (2/823) • Hypothyroidism • 2 patients with myopathy at 80-mg dose had an elevated TSH

19. CK > 10 × ULN Frequency by % LDL-C Reduction Cerivastatin (0.2 - 0.8 mg) Atorvastatin (10 - 80 mg) Rosuvastatin (5 - 80 mg) Pravastatin (40 - 80 mg) Simvastatin (40 - 80 mg) % Prescribing Information and Summary Basis of Approval documents. Heart Protection Study. Lancet. 2002;360:7-22.

20. Summary of Effects of Rosuvastatin on Skeletal Muscle • At rosuvastatin doses up to and including 40 mg, safety profile similar to marketed statins • Greater lipid modification achieved with rosuvastatin • Increased frequency of adverse effects at the 80-mg dose • 2% to 4% additional LDL-C lowering achieved compared with 40 mg • Well tolerated in patients < 65 yr old • All patients recovered

21. Safety Presentation Agenda • Demographics • Exposure • Adverse events • Liver effects • Skeletal muscle effects • Renal effects • Drug-drug interactions

22. Background (1) • Observed increased frequency of proteinuria at the 80-mg dose • Important questions addressed in this section • Frequency • Magnitude • Nature • Short-term and long-term consequences

23. Background (2) • Background prevalence of proteinuria is up to 10% on routine dipstick urinalysis • Proteinuria can have a functional or organic cause • Proteinuria can have a glomerular or tubular etiology • Glomerular proteinuria caused by leakage of albumin and other larger-molecular-weight proteins • Tubular proteinuria caused by reduced reabsorption of normally filtered proteins

24. 32 Frequency of Proteinuria, Hematuria, and Proteinuria/Hematuria (FDA Table 15)

25. 32 Magnitude of Proteinuria Proteinuria: “none or trace” to “2+ or greater.” †Ratios × 1000 approximate excretion in mg/day.

26. Nature of Proteinuria and Hematuria • Proteinuria primarily tubular in origin • Gel electrophoresis shows a tubular pattern • Quantitation of proteins shows increased levels of low-molecular-weight proteins (α-1 microglobulin, β-2 microglobulin, RBP) • Back-titration of patients shows greatest reductions in low-molecular-weight proteins • Hematuria • Red blood cells present on microscopic evaluation • Not myoglobin • Resolves on back-titration

27. Preclinical Effects of Statins on Renal Tubules

28. Rosuva Atorva Simva Prava Fluva Effect of Statins on Albumin Uptake by OK Cells Combined result of 2 to 4 experiments, mean ± SE 24-hr exposure to statins 0 20 % inhibition 40 60 80 100 0.001 0.01 0.1 1 10 100 1000 Concentration, µM

29. Rosuva Atorva Simva Prava Fluva Inhibition of Albumin Uptake and Inhibition of Cholesterol Synthesis 100 80 60 % inhibition of albumin uptake 40 20 0 0 10 20 30 40 50 60 70 80 90 100 % inhibition of cholesterol synthesis

30. Inhibition of Statin Effects on Albumin Uptake by Mevalonate Combined results of 2 experiments, mean ± SE 120 100 80 % of control 60 40 20 0 Control Simva10 µM Simva100 µM Rosuva10 µM Rosuva100 µM Mevalonate 100 µM – + – + – + – + – +

31. Why is Tubular Proteinuria Observed With High-Dose Rosuvastatin Therapy • Rosuvastatin is a highly effective inhibitor of HMG-CoA reductase • Approximately 28% of rosuvastatin systemic clearance is renal; predominantly by tubular secretion • For other statins, the degree of renal excretion or the overall effectiveness inhibiting HMG-CoA reductase is less than that observed with rosuvastatin

32. 3 Patients With Investigator-Designated Acute Renal Failure

33. Frequency of > 30% Creatinine Elevations in Patients With Proteinuria at Last VisitCombined All Controlled/Uncontrolled and RTLD Pool Proteinuria: “none or trace” to “2+ or greater.”

34. 31 C9.4.7.1.3 Proteinuria ≥ 2+, Hematuria ≥ 1+, and > 30% Increasein Creatinine at Last Visit Combined All Controlled/Uncontrolled and RTLD Pool

35. 32 Proportion of Patients With Proteinuria, ≥ 96 Wk of Rosuvastatin TreatmentCombined All Controlled/Uncontrolled and RTLD Pool Proteinuria: “none or trace” to “2+ or greater.” †Includes patients who back-titrated from the 80-mg dose.

36. 31 Proteinuria ≥ 2+, Hematuria ≥ 1+, and > 30% Increasein Creatinine at Last Visit, ≥ 96 Wk of Rosuvastatin TreatmentCombined All Controlled/Uncontrolled and RTLD Pool C9.4.7.1.3.2, C9.9.4.7.1.3 †Includes patients who back-titrated from the 80-mg dose.

37. Abnormal Urinalysis With Renal Biopsy After Long-term TreatmentRosuvastatin 80 mg • 69-y/o South African male • History of unspecified renal disease in childhood, stasis ulcers, back pain, and heterozygous FH • Medications: aspirin, paracetamol, topical steroids, intramuscular PCN • 2 abnormal baseline urinalyses: 1 showed active sediment; other 1+ proteinuria, no active sediment • After 18 months, creatinine increased from 1.1 to a maximum of 1.6 mg/dL, urinalysis showed 3+ protein and moderate blood (last on-treatment creatinine 1.4 mg/dL) • Renal biopsy showed tubulointerstitial disease • Urinalysis abnormalities recurred after rechallenges with rosuvastatin and atorvastatin

38. 31 % Change in Creatinine at Last Value in Patients Given at Least 40 mg of Rosuvastatin by Baseline Renal FunctionCombined All Controlled/Uncontrolled and RTLD Pool

39. 9 Summary of Effects of Rosuvastatin on the Kidney • Findings of proteinuria and proteinuria/hematuria associated with rosuvastatin were thoroughly evaluated • Findings observed predominately in patients dosed above 40 mg • Rosuvastatin at doses up to and including 40 mg was well tolerated from the renal standpoint • Urinalysis or creatinine monitoring not necessary • No evidence for long-term detrimental effects on renal function

40. Safety Presentation Agenda • Demographics • Exposure • Adverse events • Liver effects • Skeletal muscle effects • Renal effects • Drug-drug interactions

41. Rosuvastatin Drug Interaction Studies—CYP450 and PgP

42. Effect of Cyclosporine on Statin Exposure Ratio of AUC in cyclosporine-treated patients to AUC in historical control patients

43. Effect of Gemfibrozil on Statin Plasma Concentrations Ratio of AUC in gemfibrozil-treated patients to AUC in placebo patients

44. Effect of Gemfibrozil and Fenofibrate on Rosuvastatin Plasma Concentrations Ratio of rosuvastatin AUC in fibrate-treated patients to AUC in placebo-treated patients

45. Other Pharmacokinetic Data Relevant to the Overall Safety of Rosuvastatin • Systemic (plasma) exposure unaffected by • Age • Sex • Mild / moderate renal impairment • Systemic exposure increases because of • Severe renal impairment • Severe hepatic impairment • Ethnicity • Exposure increased in Japanese patients in Japan • No differences in exposure among Caucasian, Black, or Hispanic patients

46. Safety Summary • Doses up to 80 mg thoroughly explored in a large dyslipidemic patient population (> 12,500) • Large number of elderly patients • Large number of patients with comorbidities • 5-mg to 40-mg dose range has a safety profile similar to other marketed statins • Increased frequency of some AEs at the 80-mg dose • Few drug-drug interactions • For at-risk patients, specific labeling information

47. Benefits of Rosuvastatin (10 mg to 40 mg) • Excellent lipid-modifying effects • At the starting dose • Across the dose-range • High percentage of patients achieve goal • At the starting dose • Across the dose-range • Provides additional lipid modification compared with existing statin therapies • eg, further LDL-C, non-HDL-C reduction

48. Rosuvastatin 10 mg Is an Appropriate Starting Dose for Most Patients With Dyslipidemia • Overall favorable benefit-risk profile • Additional efficacy compared with 5-mg dose • Better lipid-modifying effects • More patients brought to NCEP goal • No difference in safety compared with 5-mg dose • For patients on cyclosporine, a 5-mg dose is available

49. Rosuvastatin 40 mg Is an Appropriate Top Dose for Patients With Dyslipidemia • Provides additional lipid-modifying benefits compared with 20-mg dose • Dose studied in > 4000 patients • > 2000 initiated therapy at this dose • Important dose for those patients who do not achieve necessary lipid modification at lower doses • Dose well tolerated