Archived – Risk of Cardiovascular Toxicity Associated with Schizophrenia Medication Clozapine – For the Public

IMPORTANT DRUG SAFETY INFORMATION FOR CONSUMERS

January 18, 2002

Risk of Cardiovascular Toxicity Associated with Schizophrenia Medication Clozapine

Novartis recommends physicians and patients to be alert for symptoms

DORVAL, Quebec (January 18, 2002) - After discussions with Health Canada, Novartis Pharmaceuticals Canada is alerting schizophrenia patients/guardians and physicians of emerging safety information concerning the cardiac effects of clozapine, a medication sold in Canada under the tradename Clozaril®. Clozaril is an atypical antipsychotic medication, prescribed for patients with treatment-resistant schizophrenia. Clozaril has been available in Canada since 1991.

Analysis of safety databases suggests that the use of clozapine is associated with an increased risk of myocarditis, an inflamation of the muscular walls of the heart. Clozapine is associated with this increased risk especially during, but not limited to, the first month of therapy. Specifically, myocarditis has been reported in patients 19 years of age and older, at dosages within the approved dosage range and during titration of clozapine. In Canada, there have been 9 reported cases of myocarditis. Of these, three have been fatal. Given the estimated 15,600 Canadian clozapine-treated patients as of August 2001, this represents an estimated incidence of 0.06% for all reports of myocarditis (or 1/1667 patients) and 0.02% for myocarditis fatalities (or 1/5200).

Other cardiovascular events, including pericarditis, pericardial effusion and cardiomyopathy have also been reported in association with clozapine use, as have heart failure, myocardial infarction and mitral insufficiency; these reports include fatalities.

Patients should contact their physician immediately if they develop persistent tachycardia (rapid heart rate) at rest accompanied by other signs and symptoms of heart failure (e.g. chest pain, shortness of breath, swelling of the ankles and feet, or arrhythmias (abnormal heart rhythms).

Other symptoms which may be present in addition to the above include fatigue, flu-like symptoms, fever that is otherwise unexplained, hypotension (low blood pressure) and/or raised jugular venous pressure (bulging neck veins when sitting or standing). Patients are advised to contact their physician before discontinuing any medication.

The occurrence of such signs and symptoms necessitates an urgent diagnostic evaluation for myocarditis, cardiomyopathy and/or other cardiovascular dysfunction by a cardiologist (NOTE: referral to cardiologist will be needed by treating physician). Patients with a family history of heart failure should have a cardiac evaluation prior to commencing treatment; clozapine is contraindicated in patients with severe cardiac disease.

The occurrence of myocarditis and other cardiovascular-related adverse events in association with Clozaril has been included in the Product Monograph since the launch of the product in Canada in 1991. The monograph has since been updated several times to provide further information on emerging safety data regarding myocarditis, the last update being issued in June 2000. Novartis is committed to patient safety, and is now alerting patients/caregivers to be aware of possible symptoms of these potentially fatal conditions, including cardiomyopathy, and to discuss them with their physicians.

Novartis has sent a health care professional letter to Canadian physicians and pharmacists alerting them of these important side effects associated with Clozaril to enable them to optimally counsel patients. The Product Monograph for Clozaril will also be expanded to provide additional background information on the association of cardiovascular toxicty and Clozaril and valuable information for prescribers on the management of myocarditis and other cardiovascular-related events. The updated full prescribing information for Clozaril for healthcare professionals and the information for the patient/guardian will be posted at http://www.novartis.ca shortly.

About Novartis

Novartis Pharmaceuticals Canada Inc., a leader in the healthcare field, is committed to the discovery, development and marketing of innovative products to improve the well being of all Canadians. Novartis Pharmaceuticals Canada conducts hundreds of clinical trials across the country seeking new treatments for cardiovascular disease, diabetes, cancer, organ transplantation and glaucoma. In 2000, the Company invested close to $34 million in research and development. Novartis Pharmaceuticals Canada Inc. employs over 700 people in Canada and its headquarters are located in Dorval, Quebec. The Novartis Group (NYSE:NVS) is also represented in Canada by Novartis Animal Health Canada Inc., Novartis Consumer Health Canada Inc., (including Novartis Nutrition Corporation and Gerber (Canada) Inc.), and CIBA Vision Canada Inc.

For further information, please contact:

Jason Jacobs

Director, Communications

Novartis Pharmaceuticals Canada Inc.

Tel.: (514) 633-7872

Any suspected adverse reactions can also be reported to:

Canadian Adverse Drug Reaction Monitoring Program (CADRMP)

Marketed Health Products Directorate

HEALTH CANADA

Address Locator: 0201C2

OTTAWA, Ontario, K1A 1B9

Tel: (613) 957-0337 or Fax: (613) 957-0335

Toll free for consumers and health professionals:

Tel: 866 234-2345, Fax: 866 678-6789

cadrmp@hc-sc.gc.ca

The ADR Reporting Form can be found in The Canadian Compendium of Pharmaceuticals and Specialties, or on the TPD website, along with the ADR Guidelines.