# Presentation: 743623

## CRESTOR®Safety

**Howard G. Hutchinson, MD**
**Vice President, Clinical Research**

## 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

**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**

**Objectives of the Rosuvastatin Clinical Development Program**

## 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**

**9**

## Safety Presentation Agenda

**Demographics**
**Exposure**
**Adverse events**
**Liver effects**
**Skeletal muscle effects**
**Renal effects**
**Drug-drug interactions**

## Demographic Characteristics of Patients (1)Combined All Controlled/Uncontrolled and RTLD Pool 

| Demographiccharacteristic | RosuvastatinN = 12,569 |
| --- | --- |
| Age, yr |  |
| Mean (SD) | 58.1 (11.8) |
| Age distribution, n (%) |   |
| < 65 yr | 8633 (68.7) |
| ≥ 65 yr | 3936 (31.3) |
| ≥ 75 yr | 915 (7.3) |
| Sex, n (%) |   |
| Male  | 6626 (52.7) |
| Female  | 5943 (47.3) |
|    Postmenopausal | 4019 (67.6) |

**9**

- PTT C1.4.1 andC1.4.2

## Demographic Characteristics of Patients (2)Combined All Controlled/Uncontrolled and RTLD Pool

| Demographic characteristic | RosuvastatinN = 12,569 |
| --- | --- |
| Ethnic origin, n (%) |  |
| Caucasian | 11,081 (88.2) |
| Hispanic | 297 (2.4) |
| Black | 820 (6.5) |
| Asian | 234 (1.9) |
| Other | 137 (1.1) |

**9**

- PTT C1.4.1 andC1.4.2

## Baseline Medical Conditions of InterestCombined All Controlled/Uncontrolled and RTLD Pool

| Medical condition | Rosuvastatin, n (%)N = 12,569 |
| --- | --- |
| Renal impairment† |         6603 (52.5) |
|    Mild (CrCl 50 to ≤ 80 mL/min) |         5579 (44.4) |
|    Moderate (CrCl 30 to < 50 mL/min) |           983 (7.8) |
|    Severe (CrCl < 30 mL/min) |             41 (0.3) |
| Hypertension |         6529 (51.9) |
| Cardiovascular disease |         4530 (36.0) |
| Diabetes |         2080 (16.5) |

**9**

- PTT C1.4.4 andC1.4.6

**†****Creatinine clearance (CrCI) derived using Cockcroft-Gault formula.**

## Maximum Continuous Duration of TreatmentCombined All Controlled/Uncontrolled and RTLD Pool

| Cumulativeduration oftreatment | Rosuvastatin daily dose |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | 5 mgN = 1325 | 10 mgN = 7819 | 20 mg N = 3939 | 40 mg N = 4007 | 80 mg N = 1583 | ≥ 40 mg N = 4338 |
| ≥ 12 wk | 995 | 6219 | 2143 | 2758 | 1055 | 2996 |
| ≥ 24 wk | 647 | 5041 | 1353 | 1893 | 971 | 2148 |
| ≥ 48 wk | 542 | 4055 | 545 | 276 | 891 | 1165 |
| ≥ 72 wk | 324 | 1546 | 235 | 159 | 783 | 1007 |
| ≥ 96 wk | 283 | 903 | 120 | 110 | 642 | 874 |
| Patient-yrof treatment | 1315 | 7458 | 1800 | 1857 | 1944 | 3792 |

**9**

- PTT C2.4.3 and C2.4.4

**Total patients – 12,569**
**Total patient-yr – 14,231**

## 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**

## Safety Presentation Agenda

**Demographics**
**Exposure**
**Adverse events**
**Liver effects**
**Skeletal muscle effects**
**Renal effects**
**Drug-drug interactions**

## 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**

## Persistent ALT Elevations by DoseCombined All Controlled/Uncontrolled and RTLD Pool

| Rosuvastatin dose | N | > 3 × ULN on 2 occasions, % |
| --- | --- | --- |
|   5 mg |    1317 | 0.5 |
| 10 mg |    7726 | 0.1 |
| 20 mg |    3882 | 0.1 |
| 40 mg |    3700 | 0.2 |
| 80 mg |    1574 | 1.4 |
| Total | 12,458 | 0.4 |

## Persistent ALT > 3 × ULN Frequency by % LDL-C Reduction

**Ref: Prescribing Information and Summary Basis of Approval documents.**

## Safety Presentation Agenda

**Demographics**
**Exposure**
**Adverse events**
**Liver effects**
**Skeletal muscle effects**
**Renal effects**
**Drug-drug interactions**

## 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**

## CK > 10 × ULN by DoseCombined All Controlled/Uncontrolled and RTLD Pool

| Rosuvastatindose | N | > 10 × ULN, % |
| --- | --- | --- |
|   5 mg | 1317 | 0.4 |
| 10 mg | 7727 | 0.2 |
| 20 mg | 3883 | 0.2 |
| 40 mg | 3700 | 0.3 |
| 80 mg | 1574 | 1.9 |
| Total  | 12,457 | 0.6 |

**9**

## Cases of MyopathyCombined All Controlled/Uncontrolled and RTLD Pool

|  |  | Patients with myopathy |  |
| --- | --- | --- | --- |
| Rosuvadose | N | All cases,n (%) | Possibly treatmentrelated, n (%)  |
| 5 mg  |    1317 |   3 (0.2) | 	0 |
| 10 mg  |    7727 |   8 (0.1) | 	0 |
| 20 mg  |    3883 |   5 (0.1) | 	1 	(0.03) |
| 40 mg  |    3700 |   5 (0.1) | 	1 	(0.03) |
| 80 mg  |    1574 | 16 (1.0) | 	11 	(0.7) |
| Total  | 12,457 | 37 (0.3)  | 	13 	(0.1) |

**CK elevations > 10 × ULN plus muscle symptoms.**

**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**

**9**

## CK > 10 × ULN Frequency by % LDL-C Reduction

**Prescribing Information and Summary Basis of Approval documents.**
**Heart Protection Study. *****Lancet*****. 2002;360:7-22.**

**%**

**Cerivastatin (0.2 - 0.8 mg)**

**Rosuvastatin (5 - 80 mg)**

**Pravastatin (40 - 80 mg)**

**Atorvastatin (10 - 80 mg)**

**Simvastatin (40 - 80 mg)**

## 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**

## Safety Presentation Agenda

**Demographics**
**Exposure**
**Adverse events**
**Liver effects**
**Skeletal muscle effects**
**Renal effects**
**Drug-drug interactions**

## 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**

## 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**

## Frequency of Proteinuria, Hematuria, and Proteinuria/Hematuria (FDA Table 15)

| Treatment | Dose | N | Urine protein≥ 2+, % | Urine blood ≥ 1+, % | Proteinuria ≥ 2+ andhematuria ≥ 1+, % |
| --- | --- | --- | --- | --- | --- |
| Placebo |  | 372 | 3.0 | 5.0 | 0 |
| Rosuvastatin |   5 mg
10 mg
20 mg
40 mg
80 mg | 653
1202
1460
2384
804 | 1.0
2.0
2.0
4.0
12.0 | 6.0
7.0
4.0
10.0
12.0 | 0
0.3
0.3
1.3
6.1 |
| Atorvastatin | 10 mg
20 mg
40 mg
80 mg | 710
667
245
377 | 2.0
2.0
0.4
0.5 | 4.0
3.0
2.0
2.0 | 0.6
0.3
0.4
0 |
| Simvastatin | 20 mg
40 mg
80 mg | 517
356
337 | 4.0
2.0
0.6 | 5.0
5.0
8.0 | 0.6
0.8
0.3 |
| Pravastatin | 20 mg
40 mg | 191
67 | 1.0
0 | 7.0
4.0 | 0.5
0 |

**32**

## Magnitude of Proteinuria

|  | N | Mean (SD) | Median | 10th - 90th percentile |
| --- | --- | --- | --- | --- |
| Protein/creatinine†(mg/mg) | 278 | 0.8 (0.55) | 0.6 | 0.2 - 1.5 |
| Albumin/creatinine†(mg/mg) | 271 | 0.3 (0.22) | 0.2 | 0.1 - 0.5 |

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

**32**

## 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**

## Preclinical Effects of Statins on Renal Tubules

| Drug | Species  | Main effects |
| --- | --- | --- |
| Rosuvastatin | Rat, dog, rabbit, cynomolgus monkey | Tubular degeneration, tubular epithelial cell changes |
| Lovastatin | Rabbit | Tubular necrosis |
| Pravastatin | Rat, rabbit, cynomolgus monkey | Nephropathy, proximal tubule cell necrosis |
| Simvastatin | Mouse, dog, rabbit | Tubular epithelial vacuolation, tubular distention |
| Fluvastatin | Rat, dog, rabbit | Tubular degeneration, epithelial hyperplasia |
| Cerivastatin | Rat, mini-pigs | Dilated tubules, tubular degeneration |
| Atorvastatin | Rat, dog | Dilatation of tubules |

## Effect of Statins on Albumin Uptake by OK Cells

**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**

**40**

**60**

**80**

**100**

**0.001**

**0.01**

**0.1**

**1**

**10**

**100**

**1000**

**Concentration, μM**

**% inhibition**

## Inhibition of Albumin Uptake and 

**Inhibition of Cholesterol Synthesis **

**0**

**20**

**40**

**60**

**80**

**100**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**% inhibition of cholesterol synthesis**

**% inhibition of albumin uptake**

## Inhibition of Statin Effects on 

**Mevalonate 100 μM**

**Combined results of 2 experiments, mean ± SE**

**Inhibition of Statin Effects on **
**Albumin Uptake by Mevalonate**

**–       ****+**

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**% of control**

**Control**

**Simva****10 μM**

**Simva****100 μM**

**Rosuva****10 μM**

**Rosuva****100 μM**

**–       ****+**

**–       ****+**

**–       ****+**

**–       ****+**

## 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**

## Patients With Investigator-Designated Acute Renal Failure

| Rosuvadose  | Number of cases | Cause |
| --- | --- | --- |
|   5 mg | 1 | Cardiogenic shock |
| 10 mg | 1 | Volume depletion |
| 20 mg | 1 | Post-CABG |
| 40 mg | 2 | 1 motor vehicle accident (sepsis)
1 recurrent kidney stones |
| 80 mg | 6 | 4 myopathy
2 uncertain |

**3**

## Frequency of > 30% Creatinine Elevations in Patients With Proteinuria at Last VisitCombined All Controlled/Uncontrolled and RTLD Pool

|  | Last visit |  |  |
| --- | --- | --- | --- |
| Rosuva
dose | N | Proteinuria,
n (%) | Creatinineincrease > 30%, n |
|   5 mg |   549 |   1 (0.2) | 0 |
| 10 mg | 1822 | 10 (0.5) | 0 |
| 20 mg | 1253 | 11 (0.9) | 2 |
| 40 mg | 2824 | 32 (1.1) | 0 |
| 80 mg |   249 | 22 (8.8) | 11 |

**Proteinuria: “none or trace” to “2+ or greater.”**

## Proteinuria ≥ 2+, Hematuria ≥ 1+, and > 30% Increasein Creatinine at Last Visit Combined All Controlled/Uncontrolled and RTLD Pool

**C9.4.7.1.3**

- 31

| Rosuvadose | N | Urine protein ≥ 2+, urine blood ≥ 1+,n (%) | Creatinine increase > 30%, n |
| --- | --- | --- | --- |
|   5 mg | 493 | 0 | 0 |
| 10 mg | 1707 | 1 (0.1) | 0 |
| 20 mg | 1194 | 1 (0.1) | 1 |
| 40 mg | 2679 | 6 (0.2) | 0 |
| 80 mg | 215 | 12 (5.6) | 8 |

## Proportion of Patients With Proteinuria, ≥ 96 Wk of Rosuvastatin TreatmentCombined All Controlled/Uncontrolled and RTLD Pool

| Rosuvadose | N | Any time, n (%) | Last visit,n (%) | Creatinine increase > 30%, n |
| --- | --- | --- | --- | --- |
|   5 mg | 261 | 3 (1.1) | 0 | 0 |
| 10 mg | 838 | 17 (2.0) | 4 (0.5) | 0 |
| 20 mg | 112 | 5 (4.5) | 1 (0.9) | 0 |
| 40 mg | 100 | 4 (4.0) | 2 (2.0) | 0 |
| 80 mg | 590 | 99 (16.8) | 37 (6.3) | 7 |
| ≥ 40 mg† | 807 | 136 (16.9) | 10 (1.2) | 0 |

**Proteinuria: “none or trace” to “2+ or greater.”**
**†****Includes patients who back-titrated from the 80-mg dose.**

**32**

## Proteinuria ≥ 2+, Hematuria ≥ 1+, and > 30% Increasein Creatinine at Last Visit, ≥ 96 Wk of Rosuvastatin Treatment Combined All Controlled/Uncontrolled and RTLD Pool

**C9.4.7.1.3.2, C9.9.4.7.1.3**

- 31

|  |  | Last visit |  |
| --- | --- | --- | --- |
| Rosuvadose | N | Urine protein ≥ 2+, urine blood ≥ 1+,
n (%) | Creatinine increase > 30%, n |
|   5 mg | 229 | 0 | 0 |
| 10 mg | 781 | 1 (0.1) | 0 |
| 20 mg | 103 | 0 | 0 |
| 40 mg | 98 | 1 (1.0) | 0 |
| 80 mg | 562 | 13 (2.3) | 5 |
| ≥ 40 mg† | 761 | 2 (0.3) | 0 |

**†****Includes patients who back-titrated from the 80-mg dose.**

## Abnormal Urinalysis With Renal Biopsy After Long-term TreatmentRosuvastatin 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**

## % Change in Creatinine at Last Value in Patients Given at Least 40 mg of Rosuvastatin by Baseline Renal FunctionCombined All Controlled/Uncontrolled and RTLD Pool

|  |  | ≥ 96 wk |  |  |
| --- | --- | --- | --- | --- |
| Renal function |  | N | Mean (SD)% change | > 30%increase, % |
|  |  |  |  |  |
| Normal |  | 456 | –5.9 (12.5) | 0.4 |
| Impaired |  | 415 | –5.3 (10.7) | 0.2 |
| 	Mild |  | 366 | –5.3 (10.7) | 0.3 |
| 	Moderate |  |   46 | –4.9 (10.9) | 0 |
| 	Severe |  |    3 | –13.7 (8.1) | 0 |

- 31

## 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**

**9**

## Safety Presentation Agenda

**Demographics**
**Exposure**
**Adverse events**
**Liver effects**
**Skeletal muscle effects**
**Renal effects**
**Drug-drug interactions**

## Rosuvastatin Drug Interaction Studies—CYP450 and PgP

| Drug | Characteristic | Effect on AUC |
| --- | --- | --- |
| Ketoconazole | 3A4 and PgP inhibitor | Not significant |
| Erythromycin | 3A4 and PgP inhibitor | 0.2-fold decrease |
| Fluconazole | 2C9 and 2C19 inhibitor | Not significant |
| Digoxin | PgP substrate | Not significant |

## Effect of Cyclosporine on Statin Exposure

**Effect of Cyclosporine on Statin Exposure**

**Ratio of AUC in cyclosporine-treated patients to **
**AUC in historical control patients **

## Effect of Gemfibrozil on Statin Plasma Concentrations

**Effect of Gemfibrozil on ****Statin Plasma Concentrations**

**Ratio of AUC in gemfibrozil-treated patients to AUC in placebo patients **

## Effect of Gemfibrozil and Fenofibrate on Rosuvastatin Plasma Concentrations

**Ratio of rosuvastatin AUC in fibrate-treated ****patients ****to AUC in placebo-treated patients**

## 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**

## 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**

## 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**

## 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**

## 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**