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Title: Health Canada Endorsed Important Safety Information on Iressa (Gefitinib)

"Health Canada Endorsed Important Safety Information on Iressa (Gefitinib)"

Subject: Lack of Survival Benefit and Increased Incidence of Tumour Haemorrhage in Association with Iressa® in Patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) OTTAWA, CANADA -- December 12, 2006 -- AstraZeneca, following discussions with Health Canada, is informing health care professionals of new safety information regarding Iressa (gefitinib). Iressa is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Although Iressa is indicated for the treatment of locally advanced non-small cell lung cancer in patients who have failed two prior chemotherapy regimens, its use has been restricted by Health Canada to patients who are currently benefiting from Iressa and whose tumours are EGFR expression status positive or unknown. For continued supply of the drug, patients have had to be registered by a pharmacist into the Iressa Patient Registry (IPR) program. Head and neck cancer is not an approved indication for Iressa, but patients with this diagnosis could have been registered if benefiting from therapy. This letter is to inform health care professional involved in the IPR, of the top-line results from an Iressa study in patients with squamous cell carcinoma of the head and neck (SCCHN) entitled: A phase 3 randomized, stratified, parallel-group, multi-centre, comparative study of Iressa 250 mg and 500 mg versus methotrexate for previously treated patients with squamous cell carcinoma of the head and neck (1839IL/0704, IMEX). · IMEX trial results demonstrate lack of survival advantage for Iressa 250 mg and 500 mg versus methotrexate in patients with squamous cell carcinoma of the head and neck. · IMEX trial results identify a potential new safety finding of tumour haemorrhage in patients treated with Iressa 250 mg and 500 mg compared to methotrexate. · Patients with head and neck cancer who are taking Iressa should be informed of the IMEX trial results by their physicians; and, where appropriate, alternative treatment options should be discussed. The objectives of the IMEX trial were to examine the efficacy and safety/tolerability of Iressa 250 mg and 500 mg versus methotrexate in a refractory, unselected population of patients with recurrent SCCHN. A total of 486 patients were recruited from approximately 100 centres worldwide; 483 patients were evaluable for safety. The trial was designed to demonstrate superiority for Iressa versus methotrexate for the primary endpoint of overall survival (OS). The trial results did not demonstrate an improvement in survival for Iressa 250 mg or 500 mg compared to methotrexate, although there was some evidence of anti-tumour activity as measured by response rate. There was a numerical advantage for patients randomized to methotrexate, which did not reach statistical significance. The median survival times were consistent with published data for active monotherapy treatments in the recurrent disease setting and are presented below: · Iressa 250 mg versus methotrexate OS: Median OS 5.6 vs. 6.7 months (HR 1.22; 95% CI 0.95 to 1.57; p= 0.1205) · Iressa 500 mg versus methotrexate OS: Median OS 6.0 vs. 6.7 months (HR 1.12; 95% CI 0.87 to 1.43; p= 0.3899) Analysis of the safety data from the IMEX trial identified a potential new safety finding of "tumour haemorrhage" in patients treated with Iressa 250 mg and 500 mg. The incidence of tumour haemorrhage seen in the Iressa 250 mg & 500 mg treated patients was; 8.9% (n=14/158) and 11.4% (n=19/166) respectively, compared to 1.9% (n=3/159) seen in the methotrexate treated patients. The majority of these tumour haemorrhages were considered by the reporting physician to be mild to moderate in nature (CTC grades 1 or 2), and resolved whilst study treatment continued. Of the 36 patients with tumour haemorrhage, 3 died as a result of their tumour haemorrhage; 2 of these 3 patients were receiving Iressa 250 mg and the third was receiving Iressa 500 mg. These 3 cases were not considered by the reporting physician to be causally related to Iressa therapy. AstraZeneca is undertaking a comprehensive review of the IMEX study data to fully understand the significance of these findings. As a Health Care Professional involved in the Iressa Patient Registry program, Health Canada, in collaboration with AstraZeneca, has requested that you be made aware of the IMEX trial results and that you communicate these results to any patient currently receiving Iressa for the treatment of SCCHN. Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any occurrence of serious and/or unexpected adverse reactions in patients receiving Iressa should be reported to AstraZeneca Canada Inc., 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 www.astrazeneca.ca 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 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. For other inquiries related to this communication, please contact Health Canada at: Therapeutic Products Directorate Tel: (613) 941-3171 Fax: (613) 941-1365 E-mail: BMORS_Enquiries@hc-sc.gc.ca Any questions or require additional information regarding Iressa®, should be addressed to AstraZeneca Medical Information at 1-800-668-6000 (English) and/or 1-800-461-3787 (French). Iressa® and the AstraZeneca logo are trademarks of the AstraZeneca group of companies. SOURCE: Health Canada

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