Important Safety Information Regarding Reports of Serious Hepatic Events in Patients Receiving ACCOLATE® (Zafirlukast) – For Health Professionals

Health Canada Endorsed Important Safety Information on ACCOLATE^® (zafirlukast)

April 14, 2004

Subject: Important Safety Information Regarding Reports of Serious Hepatic Events in Patients Receiving ACCOLATE^® (zafirlukast)

Dear Health Care Professional,

AstraZeneca Canada Inc. in consultation with Health Canada would like to update you on important safety information from post marketing experience with Accolate^® (zafirlukast). From 1997 to December 31, 2003, one (1) case of hepatitis, 4 cases of hepatobiliary disorders or possible hepatitis, 1 case of hydrocholecystis and 4 cases of elevated liver enzymes have been reported in Canadian patients receiving Accolate^®. These cases did not result in fatal outcome and there have been no new significant liver dysfunction post-marketing reports submitted in Canada since April 2002. From worldwide post-marketing surveillance that includes Canadian reports, there were a total of 46 reports of hepatitis, 14 reports of liver failure, 3 of which progressed from fulminant hepatitis, and 59 reports of other significant liver dysfunction*. A fatal outcome was seen in 7 cases. The preceding data are provided notwithstanding that pre-existing conditions and/or concomitant therapies may have caused the hepatic events or contributed to them. The exposure to Accolate^® is estimated to be more than 1.9 million patient years worldwide and more than 54,800 patient years in Canada. The following is an update to the information about hepatic events provided in Accolate^® Product Monograph and in ‘Dear Healthcare Professional Letter' issued on October 7, 2002.

• Elevations in serum transaminases have been reported during treatment with Accolate^®. These were usually asymptomatic and transient but could represent early evidence of hepatotoxicity and very rarely have been associated with more severe hepatocellular injury, fulminant hepatitis and liver failure, resulting in some cases in fatal outcome.
• In some post-marketing cases of more severe hepatic injury, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede these observations.
• In most, but not all, post-marketing reports, the patient's symptoms abated and the liver enzymes returned to normal or near normal after stopping Accolate^®.
• In very rare cases, patients have progressed to fulminant hepatitis and/or hepatic failure despite early detection of liver enzyme elevations or signs and symptoms and/or discontinuation of Accolate^®.
• It is important that physicians be informed and subsequently inform their patients to be alert to the signs and symptoms of hepatic injury and to seek immediate medical attention if these signs or symptoms develop. Although periodic serum transaminase testing has not proven to prevent serious injury, serum transaminase testing should be done at baseline and periodically during Accolate^® treatment.
• The appearance of signs and symptoms of hepatotoxicity or development of abnormal transaminase and/or bilirubin levels while on Accolate^® treatment is an indication for immediate termination of Accolate^® and close monitoring of patient. The serum transaminases, in particular serum ALT, should be measured immediately and the patient managed accordingly.

Reporting rates determined on the basis of spontaneously reported post-marketing adverse events are generally presumed to underestimate the risks associated with drug treatments.

Accolate^® belongs to a class of drugs called leukotriene receptor antagonists and is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Accolate^® was launched globally in 1996 and was launched in Canada in 1997.

The Product Monograph for Accolate^® has been revised to include more specific recommendations for patient management. Please note the following:

Under "WARNINGS/Hepatic Effects"

"Elevations in serum transaminases can occur during treatment with ACCOLATE. These were usually asymptomatic and transient but could represent early evidence of hepatotoxicity and have very rarely (less than 1 case / 10,000 patient years) been associated with more severe hepatocellular injury, fulminant hepatitis and liver failure. In some post-marketing cases of more severe hepatic injury, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede these observations. The following hepatic events (which have occurred predominantly in females) have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose of ACCOLATE (40 mg/day): very rare (less than 1 case / 10,000 patient years) cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and very rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all, post-marketing reports, the patient's symptoms abated and the liver enzymes returned to normal or near normal after stopping ACCOLATE. In very rare (less than 1 case / 100,000 patient years) cases, patients have progressed to fulminant hepatitis and/or hepatic failure despite early detection of liver enzyme elevations or signs and symptoms and/or discontinuation of ACCOLATE."

"It is important that physicians be informed and subsequently inform their patients to be alert to the signs and symptoms of hepatic injury [e.g., right upper quadrant abdominal pain (enlarged liver), nausea, vomiting, fatigue, lethargy, pruritus, jaundice, ‘flu-like' symptoms, anorexia, dark urine, discoloured and/or pale stools], and to seek immediate medical attention if these signs or symptoms develop. The appearance of signs and symptoms of hepatotoxicity or development of abnormal aminotransferase and/or bilirubin levels while on treatment is an indication for immediate termination of ACCOLATE treatment and close monitoring of patient. The serum transaminases, in particular serum ALT, should be measured immediately and the patient managed accordingly. Serum transaminase testing should be done at baseline and periodically during ACCOLATE treatment. Periodic serum transaminase testing has not proven to prevent serious injury."

"If liver function tests are consistent with hepatic dysfunction, ACCOLATE therapy should not be resumed. Patients in whom ACCOLATE is discontinued due to hepatotoxicity where no other attributable cause is identified, should not be re-exposed to ACCOLATE. ACCOLATE is not recommended for patients with hepatic impairment including hepatic cirrhosis."

Under "Information for the patient / undesirable effects that may be experienced with accolate"

A section about hepatic effects has been updated to urge the patient to report the listed events to the physician immediately. A statement was also added that reads "Very rarely severe liver injury, including liver failure (which may result in a fatal outcome), has been observed."

The identification, characterization, and management of marketed health product-related adverse reactions are dependent on the active participation of health care professionals in adverse reaction reporting programmes. Any occurrences of hepatic dysfunction in patients receiving Accolate^® should be reported to AstraZeneca or Health Canada at the following addresses:

AstraZeneca Canada Inc.

1004 Middlegate Road

Mississauga, Ontario

L4Y 1M4

Tel: 1-800-433-0733

Fax: 1-800-267-5743

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

Email: 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.

If you have concerns regarding the content of this letter, please address them in writing and forward them via facsimile transmittal or email to the contact person listed above.

Any questions or requests for the revised Product Monograph may be directed to Medical Information via AstraZeneca Canada Inc. Customer Service at 1-800-668-6000 (English) or 1-800-461-3787 (French).

Sincerely,

original signed by

Kazimierz R. Borkowski, Ph.D.

Vice President, Medical Affairs

AstraZeneca Canada Inc.

ACCOLATE^® is a trademark, the property of the AstraZeneca group.

* Reports of other significant liver dysfunction are defined as reports of symptoms or signs of clinical hepatitis (e.g. anorexia, nausea, vomiting, right upper quadrant pain, fatigue, lethargy, flu-like symptoms, enlarged liver, pruritus and jaundice) and may have been associated with elevated liver function tests.