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CRESTOR®
Safety
Howard G. Hutchinson, MDVice President, Clinical Research
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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
Objectives of the Rosuvastatin Clinical Development Program
CS-3
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
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Safety Presentation Agenda
Demographics
Exposure
Adverse events
Liver effects
Skeletal muscle effects
Renal effects
Drug-drug interactions
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Demographic Characteristics of Patients (1)Combined All Controlled/Uncontrolled and RTLD Pool
Demographiccharacteristic
RosuvastatinN = 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)
9P
TT
C1.
4.1
andC
1.4.
2
CS-6
Demographic Characteristics of Patients (2)Combined All Controlled/Uncontrolled and RTLD Pool
Demographic characteristic
RosuvastatinN = 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)
9P
TT
C1.
4.1
andC
1.4.
2
CS-7
Baseline Medical Conditions of InterestCombined All Controlled/Uncontrolled and RTLD Pool
Medical conditionRosuvastatin, 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)
9P
TT
C1.
4.4
andC
1.4.
6
†Creatinine clearance (CrCI) derived using Cockcroft-Gault formula.
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Maximum Continuous Duration of TreatmentCombined All Controlled/Uncontrolled and RTLD Pool
Cumulativeduration oftreatment
Rosuvastatin daily dose
5 mgN = 1325
10 mgN = 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-yrof treatment
1315 7458 1800 1857 1944 3792
9P
TT
C2.
4.3
and
C2.
4.4
Total patients – 12,569
Total patient-yr – 14,231
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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
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Safety Presentation Agenda
Demographics
Exposure
Adverse events
Liver effects
Skeletal muscle effects
Renal effects
Drug-drug interactions
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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
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Persistent ALT Elevations by DoseCombined 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
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Persistent ALT > 3 × ULN Frequency by % LDL-C Reduction
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
% LDL-C reduction
% p
ersi
sten
t A
LT
> 3
× U
LN
Ref: Prescribing Information and Summary Basis of Approval documents.
Fluvastatin (20 - 80 mg)
Rosuvastatin (5 - 80 mg)
Lovastatin (20 - 80 mg)
Atorvastatin (10 - 80 mg)Simvastatin (40 - 80 mg)
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Safety Presentation Agenda
Demographics
Exposure
Adverse events
Liver effects
Skeletal muscle effects
Renal effects
Drug-drug interactions
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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
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CK > 10 × ULN by DoseCombined All Controlled/Uncontrolled and RTLD Pool
Rosuvastatindose 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
CS-17
Cases of MyopathyCombined All Controlled/Uncontrolled and RTLD Pool
Patients with myopathy
Rosuvadose N
All cases,n (%)
Possibly treatmentrelated, 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.
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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
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CK > 10 × ULN Frequency by % LDL-C Reduction
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
% LDL-C reduction
CK
> 1
0 ×
UL
N
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)
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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
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Safety Presentation Agenda
Demographics
Exposure
Adverse events
Liver effects
Skeletal muscle effects
Renal effects
Drug-drug interactions
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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
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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
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Frequency of Proteinuria, Hematuria, and Proteinuria/Hematuria (FDA Table 15)
Treatment Dose NUrine protein
≥ 2+, %Urine blood
≥ 1+, %Proteinuria ≥ 2+ and
hematuria ≥ 1+, %
Placebo 372 3.0 5.0 0
Rosuvastatin 5 mg10 mg20 mg40 mg80 mg
653120214602384
804
1.02.02.04.0
12.0
6.07.04.0
10.012.0
00.30.31.36.1
Atorvastatin 10 mg20 mg40 mg80 mg
710667245377
2.02.00.40.5
4.03.02.02.0
0.60.30.40
Simvastatin 20 mg40 mg80 mg
517356337
4.02.00.6
5.05.08.0
0.60.80.3
Pravastatin 20 mg40 mg
19167
1.00
7.04.0
0.50
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CS-25
Magnitude of Proteinuria
N Mean (SD) Median10th - 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.
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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
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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
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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
1000.001 0.01 0.1 1 10 100 1000
Concentration, µM
% i
nh
ibit
ion
RosuvaAtorvaSimvaPravaFluva
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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
% i
nh
ibit
ion
of
alb
um
in u
pta
ke
Simva
FluvaPrava
AtorvaRosuva
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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
% o
f co
ntr
ol
Control Simva10 µM
Simva100 µM
Rosuva10 µM
Rosuva100 µM
– + – + – + – +
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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
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Patients With Investigator-Designated Acute Renal Failure
Rosuvadose
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 myopathy2 uncertain
3
CS-33Frequency of > 30% Creatinine Elevations in Patients With Proteinuria at Last VisitCombined 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.”
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Proteinuria ≥ 2+, Hematuria ≥ 1+, and > 30% Increasein Creatinine at Last Visit Combined All Controlled/Uncontrolled and RTLD Pool
C9
.4.7
.1.3
31
Rosuvadose 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
CS-35Proportion of Patients With Proteinuria, ≥ 96 Wk of Rosuvastatin TreatmentCombined All Controlled/Uncontrolled and RTLD Pool
Rosuvadose 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.
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CS-36Proteinuria ≥ 2+, Hematuria ≥ 1+, and > 30% Increasein 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
.331
Last visit
Rosuvadose 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.
CS-37Abnormal 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
CS-38% 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
≥ 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
CS-39
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
CS-40
Safety Presentation Agenda
Demographics
Exposure
Adverse events
Liver effects
Skeletal muscle effects
Renal effects
Drug-drug interactions
CS-41
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
CS-42
20.0
7.4 7.2 7.1
3.8 3.1 3.0
0
4
8
12
16
20
24
Lova Atorva Prava Rosuva Ceriva Fluva Simva
Statin
AU
C r
atio
Effect of Cyclosporine on Statin Exposure
Ratio of AUC in cyclosporine-treated patients to AUC in historical control patients
CS-43
5.6
2.9 2.8
2.0 1.9
0
1
2
3
4
5
6
Cerivastatin Simvastatinacid
Lovastatin acid
Pravastatin Rosuvastatin
AU
C r
atio
Effect of Gemfibrozil on Statin Plasma Concentrations
Ratio of AUC in gemfibrozil-treated patients to AUC in placebo patients
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Effect of Gemfibrozil and Fenofibrate on Rosuvastatin Plasma Concentrations
1.07
1.90
0.00.20.40.60.81.01.21.41.61.82.0
Gemfibrozil Fenofibrate
AU
C r
atio
Ratio of rosuvastatin AUC in fibrate-treated patients to AUC in placebo-treated patients
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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
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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
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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
CS-48Rosuvastatin 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
CS-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
