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

Issues to be addressed by the Advisory Committee Safety Dosing

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

Incidence of CK elevations and myopathy seen in phase II/III (mg) CK>10xULN MYOPATHY (all cases) 0.4 1.6% 1.0-1.6% 0.8 2.1% 0.9-1.0% Pbo 0% 0% 5 0.4% 0.2% 10 0.2% 0.1% 20 0.2% 0.1% 40 0.4% 0.2% 80 1.9% 1.0% 5-80 0.03-0.9% 0-0.5% Baycol Rosuva All marketed STATINSa Data from Tables 10, 11 FDA briefing packeta

% 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

% 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

% 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

Renal adverse events 2 cases of acute renal failure of unclear etiology after 15-31 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)

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?

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

Issues to be addressed by the Advisory Committee Safety Dosing

Mean LDL-C (mg/dL) in Type IIA/IIB dyslipidemia Trials 8 and 23 pooled / Week 6 LOCF/ ITT Dose 0 1 2.5 5 10 20 40 (mg) BSL 194 191 190 191 190 191 185 Final 187 128 115 110 95 90 70 %CH -4 -33 -40 -43 -50 -53 -62

Recommended start doses STATIN Dose LDL-C Mean % Change Fluvastatin 20-40mg - 22% (20mg) - 25% (25mg) Lovastatin 20mg - 27% Pravastatin 40mg - 34% Simvastatin 20-40mg - 38% (20mg) (40mg for high risk of CHF) - 41% (40mg) Atorvastatin 10 or - 39% (10mg) 20mg - 43% (20mg) (40mg for pts needing >45%) - 50% (40mg) Rosuvastatin 10-20mg - 50% (10mg) - 53% (20mg) Data was taken from current labels for IIA & IIB dyslipidemia not placebo subtracted

Mean LDL-C change in statin therapy clinical events trials Primary prevention WOSCOPS -26% AFCAPS/TexCAPS -25% • Secondary Prevention 4S -35% CARE -32% HPS -29% LIPID -25% Rosuvastatin 5 mg -43% Ballantyne, CM Am J Cardiol 82, 3-12Q 1998 Lancet 360, 7-2, 2002

Dosing considerations AUC Cmax Cyclosporin 7x 11x Gemfibrozil 2x 2x Japanese Ancestry 2x 2x Severe Renal Failure 3x 3x (CrCL< 30ml/min) Severe Liver Failure 2-4x 4-16x (Maddrey df >54)

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

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

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?