1. CRESTOR® (ZD4522, rosuvastatin calcium) TABLETS AstraZeneca New Drug Application (21-366)
Endocrinologic & Metabolic Drugs
Advisory Committee Meeting
William Lubas M.D., Ph.D.
Center for Drug Evaluation and Research

2. Issues to be addressed by the Advisory Committee
Safety
Dosing

3. Statin associated muscle toxicity
CK elevations
Myopathy
(CK>10xULN & Muscle Symptoms)
Rhabdomyolysis
(Clinical Diagnosis)

4. Incidence of CK elevations and myopathy seen in phase II/III
(mg) CK>10xULN MYOPATHY
(all cases)
% %
% %
Pbo 0% 0%
5 0.4% 0.2%
% 0.1%
% 0.1%
% 0.2%
% 1.0%
% %
Baycol
Rosuva
All marketed STATINSa
Data from Tables 10, 11 FDA briefing packeta

5. % of patients with proteinuria ( ++) at any visit
All Patients
(n)
Simvastatin 80
337 40
356 20
517
Pravastatin 40 67
191 20 80
377
Atorvastatin 40
245 20
667 10
710 80
1258
Rosuvastatin 40
3578 20
2801
5592 10 5
988
Placebo
372
5811
Dietary Run In
% of patients
Data from AV_LUBR, i.e. All controlled/Uncontrolled & RTLD Pools

6. % of patients with proteinuria ( ++) by rosuvastatin dose (any visit) subgrouped by Cr change from baseline
Data from AV_LUBR, i.e. All controlled/Uncontrolled & RTLD Pools, OLE-Open label extension

7. % of patients with combined proteinuria ( ++) & hematuria ( +) at any visit subgrouped by Cr change from baseline
Data from AV_LUBR, i.e. All controlled/Uncontrolled & RTLD Pools, OLE-Open label extension

8. Renal adverse events
2 cases of acute renal failure of unclear etiology after days on 80mg dose (Biopsy-ATN)
1 case of chronic tubulo-interstitial nephritis after 18 months on 80mg (Biopsy-chronic interstitial inflammatory process, Positive Rechallenge Test)

9. Unanswered renal questions
Have these renal effects of rosuva been adequately characterized?
Is monitoring necessary? At higher doses? (e.g., Cr, Urinalysis)
What investigations are needed to better describe the “natural history” of this drug effect?
Is this a class effect of statins?

10. Safety Summary
The frequency of CK elevations & Myopathy at doses of 40mg or less is similar to other statins
The frequency of Cr increase of >30% seen with proteinuria (> ++) is higher in patients at doses of 80mg compared to lower doses
The OK cell experimental model does not fully explain the clinical renal effects (e.g., proteinuria, microscopic hematuria, and Cr elevation)
Serum rosuvastatin levels above levels normally seen with 40mg may be associated with renal and muscle-related adverse events

11. Issues to be addressed by the Advisory Committee
Safety
Dosing

12. Mean LDL-C (mg/dL) in Type IIA/IIB dyslipidemia Trials 8 and 23 pooled / Week 6 LOCF/ ITT
Dose (mg)
BSL
Final
%CH

13. Recommended start doses
STATIN Dose LDL-C
Mean % Change
Fluvastatin mg - 22% (20mg)
- 25% (25mg)
Lovastatin 20mg - 27%
Pravastatin 40mg %
Simvastatin mg - 38% (20mg)
(40mg for high risk of CHF) - 41% (40mg) Atorvastatin 10 or % (10mg)
20mg % (20mg)
(40mg for pts needing >45%) - 50% (40mg)
Rosuvastatin mg - 50% (10mg)
- 53% (20mg)
Data was taken from current labels for IIA & IIB dyslipidemia not placebo subtracted

14. Mean LDL-C change in statin therapy clinical events trials
Primary prevention
WOSCOPS %
AFCAPS/TexCAPS %
• Secondary Prevention
4S %
CARE %
HPS %
LIPID %
Rosuvastatin 5 mg %
Ballantyne, CM Am J Cardiol 82, 3-12Q 1998
Lancet 360, 7-2, 2002

15. Dosing considerations
AUC Cmax
Cyclosporin x x
Gemfibrozil x x
Japanese Ancestry x x
Severe Renal Failure x x
(CrCL< 30ml/min)
Severe Liver Failure x x
(Maddrey df >54)

16. Plasma rosuvastatin concentrations by dose and in 6 patients with rhabdomyolysis or renal toxicity

17. Dosing Summary Special Populations
Limit maximal doses
cyclosporin 5mg
gemfibrozil 10mg
severe RF 10mg

18. Dosing Summary Start Dose
Proposed start dose of 10mg for patients with hypercholesterolemia and mixed dyslipidemia (baseline LDL-C < 190mg/dL)
Should the 5mg dose be recommended as an alternate start dose?