Association of CRESTOR® (rosuvastatin) with Muscle -Related Adverse Events – AstraZeneca Canada Inc. – For Health Professionals

Health Canada Endorsed Important Safety Information on CRESTOR^® (rosuvastatin)

March 8, 2005

Subject: Important safety information for CRESTOR^® (rosuvastatin)

Dear Health Care Professional,

AstraZeneca Canada Inc., in consultation with Health Canada, would like to inform you of important safety information for CRESTOR^® (rosuvastatin). CRESTOR^® is a lipid-lowering agent of the statin class, which has been available in Canada since February 2003. In June 2004, AstraZeneca Canada Inc., in consultation with Health Canada, issued a letter to Canadian health care professionals advising of an association between use of CRESTOR^® (rosuvastatin) and rhabdomyolysis. A second advisory was posted to the Health Canada website in November 2004 identifying an increased reporting rate of rhabdomyolysis associated with use of the CRESTOR^® 40 mg daily dose.

Health Canada has conducted further review of safety information relating to use of CRESTOR^®, including Canadian adverse event reports, and has requested changes to the Canadian Product Monograph for CRESTOR^® (rosuvastatin) to permit the safe use of this medication.

Changes to the CRESTOR^® Product Monograph include:

• CONTRAINDICATION of the 40 mg once daily dose in patients with pre-disposing risk factors for myopathy/rhabdomyolysis.
• Recommendation that the 40 mg once daily dose be initiated under specialist supervision.
• Recommendation that all patients should be started at the recommended starting dose(s) and maintained on the lowest dose that meets their therapeutic goal.
• Recommendation of a new lower 5 mg once daily starting dose for Asian patients and patients with severe renal impairment.
• Initiation of therapy with CRESTOR^® 5 mg once daily to be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy.

Contraindications

The Canadian Product Monograph for CRESTOR^® (rosuvastatin) has been revised to contraindicate 40 mg in patients with pre-disposing factors for myopathy/rhabdomyolysis such as:

• Personal or family history of hereditary muscular disorders
• Previous history of muscle toxicity with another HMG Co-A reductase inhibitor
• Concomitant use of a fibrate or niacin
• Severe hepatic impairment
• Severe renal impairment (CrCl less than 30 ml/min/1.73 m²)
• Hypothyroidism
• Alcohol abuse
• Asian patients
• Situations where an increase in rosuvastatin plasma levels may occur

Asian patients (having either Filipino, Chinese, Japanese, Korean, Vietnamese or Asian-Indian origin) may be at greater risk of developing muscle related adverse events, including rhabdomyolysis, with CRESTOR^® (rosuvastatin) because in a recent US study, rosuvastatin drug levels were found to be elevated approximately 2-fold in Asians when compared to a Caucasian control group.

Use of CRESTOR^® at any dose continues to be contraindicated in patients with hypersensitivity to any component of this medication, with active liver disease or unexplained persistent elevations of serum transaminases, in pregnant and nursing mothers and in patients using concomitant cyclosporine.

Dosing Recommendations

When prescribing CRESTOR^®, all patients should be started at the recommended starting dose(s) and titrated to the lowest effective dose that will meet their individual therapeutic goals.

The recommended starting dose of CRESTOR^® in most patients is 10 mg once daily. Most patients achieve recommended target lipid values at this dose.

A new recommendation for initiation of therapy with CRESTOR^® 5 mg once daily is made for:

• Asian patients
• Patients with severe renal impairment

A 5 mg CRESTOR^® tablet is being introduced onto the Canadian market and will be available in May 2005. As a result, initiation of therapy with CRESTOR^® 5 mg once daily may be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy.

Patients who are switched to CRESTOR^® from treatment with another HMG-CoA reductase inhibitor should be started on 10 mg even if they were on a high dose of the previous HMG-CoA reductase inhibitor.

For patients with severe hypercholesterolemia (including those with familial hypercholesterolemia), a 20 mg start dose may be considered. These patients should be carefully followed.

A dose of CRESTOR^® 40 mg once daily should only be used in patients with severe hypercholesterolemia who do not achieve their recommended target lipid values at lower doses.

Specialist supervision is recommended if the 40 mg dose is initiated.

Product Monograph Changes Requested for All Statins

Health Canada has requested that all statin brand manufacturers complete a class Product Monograph revision due to a need for consistent safety information regarding rhabdomyolysis and myopathy. In line with actions currently being undertaken by all statin manufacturers, these class revisions have been incorporated into the revised CRESTOR^® Product Monograph. Class changes include updates to the Warnings, Precautions, and Dosage and Administration sections, which specify that some patients are at a higher risk of statin-induced myopathy and/or rhabdomyolysis.

Specifically, statins should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

• Personal or family history of hereditary muscular disorders
• Previous history of muscle toxicity with another HMG Co-A reductase inhibitor
• Concomitant use of a fibrate or niacin
• Hypothyroidism
• Alcohol abuse
• Excessive physical exercise
• Age >70 years
• Renal impairment
• Hepatic impairment
• Diabetes with hepatic fatty change
• Surgery and trauma
• Frailty
• Situations where an increase in plasma levels of "statin" may occur

The dosage of "statin" should be individualized according to baseline LDL-C, total-C/HDL-C ratio and /or TG levels to achieve the recommended target lipid values at the lowest possible dose.

The Information to the Patient leaflet has also been revised as a result of this class update. The revised leaflet will:

• Help patients recognize if they have pre-disposing factors for myopathy/rhabdomyolysis.
• Advise those patients who do have pre-disposing factors to discuss these factors with a health care professional before starting a statin
• Help patients recognize symptoms of potentially serious adverse events (myalgia, myopathy and rhabdomyolysis) for which timely consultation with a health care professional is advised.

Past Dear Health Care Professional Letters about CRESTOR^®.

Health Canada will continue to monitor the safety profile of statins, including CRESTOR^® (rosuvastatin), and will examine new safety information as it emerges. Meanwhile, it is important to remain vigilant for the possibility of muscle toxicity and to report any possible cases.

The identification, characterization, and management of marketed health product-related adverse reactions are dependent on the active participation of health care professionals in adverse drug reaction reporting programmes. Any occurrences of myopathy/rhabdomyolysis or other serious and/or unexpected adverse reactions in patients receiving CRESTOR^® should be reported to AstraZeneca Canada Inc. or Health Canada at the following addresses:

AstraZeneca Canada Inc.
1004 Middlegate Road
Mississauga, ON, L4Y 1M4
Tel: 1-800 433-0733
Fax: 1-800-267-5743
Astra Zeneca Canada Website

Any suspected adverse reaction can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701C
OTTAWA, Ontario, K1A 0K9
Tel: (613) 957-0337 or Fax: (613) 957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free:
Tel: 866 234-2345
Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

For other inquiries: please refer to contact information.

The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

Your professional commitment in this regard has an important role in protecting the well being of your patients by contributing to early signal detection and informed drug use.

If you have any questions regarding this information, please contact AstraZeneca Medical Information at 1-800-668-6000 (English) and/or 1-800-461-3787 (French).

AstraZeneca Canada Inc.

Original signed by

Kazimierz R. Borkowski, Ph.D.
Vice President, Medical Affairs

CRESTOR^® and the AstraZeneca logo are trademarks of the AstraZeneca group of companies. Licensed from Shionogi & Co Ltd, Osaka, Japan.