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CRESTOR®

(rosuvastatin calcium)

Tablets

Endocrinologic and Metabolic Drugs

Advisory Committee

Bethesda, Maryland

July 9, 2003

CRESTOR®

Introduction and
Regulatory Overview

Mark S. Eliason, MSc

Director, Regulatory Affairs

Objectives of the Rosuvastatin Clinical Development Program

• 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

Rosuvastatin Is a Hydrophilic Statin

Rosuvastatin Human Pharmacokinetics

• Absorption
  • Absolute bioavailability = 20.1%
  • T_max = 3 to 5 hr
• Distribution
  • V_ss = 134.0 L
  • Plasma protein binding = 88%
• Metabolism
  • Not extensively metabolized
• Elimination
  • t_½ = 16 to 20 hr
  • 90% in feces, 10% in urine

The NDA Clinical Program

• Large international clinical trial program
• 33 phase I trials
• 27 phase II/III trials
  • Doses of 5 to 80 mg studied in phase III
  • 12,569 patients in safety database
• Phase III trial designs
  • Comparisons with placebo, atorvastatin, simvastatin, pravastatin, niacin, fenofibrate
  • Combinations with niacin, fenofibrate, and cholestyramine
  • Open-label extension trials

Important Features of the Rosuvastatin Clinical Development Program

• All clinical laboratory samples analyzed at 1 central laboratory in the phase III program
• Trials were designed to be inclusive
  • No upper age limit for trials
  • For most trials, the upper limit for creatinine was 2.5 mg/dL
  • Women of childbearing potential participated
  • Patients with comorbidities were included provided they were stable

US Regulatory History

• Initial NDA submission (June 2001)
  • Proposed dose range of 10 to 80 mg
• In March 2002 AstraZeneca and Division agreed to
  • Suspend 80-mg development
  • Back-titrate 80-mg dose to 40 mg
• NDA Action Letter (May 2002)
  • 10-mg, 20-mg, and 40-mg doses approvable
  • Data requested on 600 patients for 20-mg and 40-mg doses each for 24 wk
  • Additional information on renal effects
• NDA amendment submitted (February 2003)
  • 12,569 patients in final phase II/III integrated database

Proposed Indications

• Primary hypercholesterolemia and mixed dyslipidemia
• Hypertriglyceridemia
• Homozygous familial hypercholesterolemia

Recommended Dosing of CRESTOR®

• The recommended starting dose of CRESTOR is 10 mg once daily, with a maximum recommended daily dose of 40 mg
• A 20-mg start dose is optional for patients with LDL-C > 190 mg/dL and aggressive lipid goals
• For homozygous familial hypercholesterolemia, the recommended starting dose of CRESTOR is 20 mg once daily
• A 5-mg dose will be made available for patients receiving cyclosporine

Current Status of CRESTOR® Program

• Market approvals currently in 24 countries
  • EU, Asia, and the Americas
  • 10- to 40-mg dose range
• Ongoing trials program
  • ~24,000 patients currently on rosuvastatin in ongoing trials in US and ROW
  • Clinical outcomes trials (18,000 patients) initiated in May 2003

Agenda for Presentation

Introduction and Regulatory Overview
Mark S. Eliason, MSc Director, Regulatory Affairs AstraZeneca
Clinical Development: Efficacy Overview
James W. Blasetto, MD, MPH Senior Director, Clinical Research AstraZeneca
Clinical Development: Safety Overview
Howard G. Hutchinson, MD Vice President, Clinical Research AstraZeneca
The Role of Rosuvastatin in Treatment of Hyperlipidemia
Daniel J. Rader, MD Associate Professor of Medicine University of Pennsylvania
 

Consultant Representatives

Daniel J. Rader, MD
Associate Professor of Medicine
University of Pennsylvania

Christie M. Ballantyne, MD
Professor of Medicine
Baylor College of Medicine

Donald B. Hunninghake, MD
Professor
Department of Pharmacology and Medicine (Cardiovascular)
University of Minnesota
Edmund J. Lewis, MD
Director, Nephrology
Professor of Medicine
Rush-Presbyterian-St. Luke’s Medical Center

Thomas Pearson, MD, PhD, MPH
Professor/Chair/Associate Dean
University of Rochester
Medical Center

Evan Stein, MD, PhD
President and CEO
Medical Research Laboratories International

see also:

FDA Health Advisory for Crestor Crestor Litigation - Crestor Lawyers - FDA Health Advisory for Crestor
Here you will find the FDA's public health advisory release on the drug Crestor by AstraZeneca.

Crestor Consumer Information Crestor FDA Consumer Information
Crestor FDA Consumer Information

Official Documents FDA Crestor commentary and Crestor News from AstraZeneca and other sources
FDA Crestor Documents and other Crestor news from official sources like AstraZeneca.