ATACAND ® (candesartan cilexetil)

1. C ATACAND®(candesartan cilexetil) Cardiovascular and Renal DrugsAdvisory Committee Bethesda, Maryland July 18, 2002

2. C ATACAND®Introduction and Regulatory Overview Cindy Lancaster, MS, MBA, JD Director, Regulatory Affairs AstraZeneca

3. Agenda for Presentation Regulatory Overview Cindy Lancaster, MS, MBA, JD Director, Regulatory Affairs AstraZeneca Comparison of Vasilios Papademetriou, MD, Antihypertensive Efficacy DSc, FACCof Candesartan Cilexetil Professor of Medicineand Losartan Georgetown University Epidemiologic and Clinical William B. Kannel, MD, FACCSignificance of Incremental Professor of Medicine andChanges in Blood Public HealthPressure Boston University School of Medicine Summary Cindy Lancaster, MS, MBA, JD Director, Regulatory Affairs AstraZeneca

4. Consultant and Sponsor Representatives Consultant • Donald Vidt, MD, FACC • Principal Investigator for Study 230 • Consultant, Department of Hypertension and Nephrology, The Cleveland Clinic Foundation • Professor of Medicine, Ohio State University AstraZeneca • Eric Michelson, MD, FACC • Senior Director, Clinical Research • Conrad Tou, PhD • Associate Director, Biostatistics • Jennifer Sugg, MS • Senior Statistical Scientist • Glenn Carlson, MD • Senior Director, Medical

5. ATACAND® (candesartan cilexetil) Selective AT1 subtype angiotensin II receptor antagonist (ARB) June 1998—Approved for the treatment of hypertension Can be used alone or in combination with other antihypertensive agents Usual recommended starting dose: 16 mg QD Introduction

6. Regulatory HistoryAgency Interactions (1) Original NDA • Included 1 positive comparative study versus losartan, SH-AHM-0001 • Randomized, double-blind, multicenter, placebo-controlled, parallel-group, 8-wk duration • Patients (N = 337) with a mean diastolic blood pressure of 95 to 114 mm Hg • Compared candesartan cilexetil 8 and 16 mg QD,losartan 50 mg QD, and placebo • The proposed labeling did not include comparator text versus losartan

7. Regulatory HistoryAgency Interactions (2) Study 175—positive results versus losartan available in 1998 • Randomized, double-blind, multicenter, titration-to-effect, parallel-group, 8-wk duration • Patients (N = 332) with a mean diastolic blood pressure of 95 to 114 mm Hg • Initiated treatment with candesartan cilexetil 16 mg QD or losartan 50 mg QD • After 4 wk, patients with a mean sitting DBP ≥ 90 mm Hg were titrated to candesartan cilexetil 32 mg QD or losartan 100 mg QD

8. Regulatory HistoryAgency Interactions (3) • August 1998 meeting with the Agency • Discussed use of SH-AHM-0001 and Study 175 to support a comparator claim versus losartan for the treatment of hypertension • SH-AHM-0001 • A starting dose comparison does not provide a meaningful comparison because the starting dose is an arbitrary point and does not represent how the drugs perform over their dose ranges • Study 175 • It was not a forced-titration design. Only poor responders would be titrated to the highest dose of the drugs in a titration-to-effect study

9. Regulatory HistoryAgency Interactions (4) Agency requirements to support comparator claim: • Establish bioequivalence of losartan and overencapsulated tablets used in blinding of comparator product • Study candesartan cilexetil and losartan at the maximum approved doses for the treatment of hypertension • Statistically significant results replicated in adequate and well-controlled trials • If once-daily dosing is studied, then the limitations should be clearly stated in promotional claims • Acceptable study designs: parallel dose-response or forced-titration

10. Description of Comparative Trials in Labeling • Results of a specific dosing regimen of once-daily administration at the maximum approved dose from 2 clinical trials with hypertensive patients • Once-daily administration is an appropriate dosing regimen for candesartan cilexetil and losartan because: • Both drugs are regularly prescribed for use once daily • Once-daily administration is the dosing regimen primarily used in on-going and completed studies • Statistically greater blood pressure reduction was demonstrated with candesartan cilexetil compared with losartan at the maximum approved dose when administered once daily • The proposed labeling is specific to effects on blood pressure reduction

11. Labeling PROPOSED ADDITION TO CLINICAL PHARMACOLOGY, Clinical Trials subsection (for insertion after the first paragraph in this section): “ Two identically designed, concurrently conducted, 8-week, multicenter, double-blind, randomized, forced-titration studies were performed to compare the antihypertensive efficacy of candesartan cilexetil and losartan at their once-daily maximum doses. Candesartan cilexetil initiated at 16 mg once daily and forced- titrated at 2 weeks to 32 mg once daily was statistically significantly more effective than losartan 50 mg once daily forced-titrated at 2 weeks to 100 mg once daily in reducing systolic and diastolic blood pressure at 8 weeks. In these studies, both agents were well tolerated.” Currently approved labeling—INDICATIONS AND USAGE: “ ATACAND is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.”

12. Regulatory Precedent Comparator Claim for ZESTRIL®/Prinivil® (lisinopril): CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension   “. . . In controlled clinical studies, ZESTRIL 20-80 mg has been compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-200 mg; and in patients with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic pressure in a population that was ¾ Caucasian. ZESTRIL was approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure, and had somewhat greater effects on systolic blood pressure.”

13. Labeling Proposed labeling is consistent with: • The general requirements of the content and format of labeling for human prescription drugs • Guidance during the design of the CLAIM program from the Division on how these studies should be described in labeling • Placement of comparator information in labeling of other antihypertensive products: • ZESTRIL®, COZAAR®, ACCUPRIL®, ALTACE®, DIOVAN®, TEVETEN® • AstraZeneca will continue to work with the Division to finalize labeling