Important Safety Information Regarding TAMIFLU® (oseltamivir phosphate) and prescription in children less than 1 year of age - Hoffmann-La Roche Limited

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Health Canada Endorsed Important Safety Information on TAMIFLU^® (oseltamivir phosphate)

February 9, 2004

Subject: IMPORTANT SAFETY INFORMATION REGARDING TAMIFLU^® (oseltamivir phosphate) AND PRESCRIPTION IN CHILDREN LESS THAN 1 YEAR OF AGE

Dear Health Care Professional:

Hoffmann-La Roche Limited, following discussions with Health Canada, would like to inform you of new preclinical safety data that have implications for the use of Tamiflu^® (oseltamivir phosphate) in very young children.

Based on new preclinical data with juvenile rats, the labelled indication of Tamiflu should be followed. Tamiflu should not be used in children less than one year of age.

Tamiflu is indicated for the treatment of acute illness due to influenza in pediatric patients 1 year and older who have been symptomatic for no more than 2 days. Tamiflu is also indicated for the prophylaxis of influenza illness in adult patients and adolescents 13 years and older following close contact with an infected individual. Tamiflu is not indicated for either treatment or prophylaxis of influenza in patients less than 1 year of age.

While the 2004 influenza season arrived earlier than in previous years, current data indicate that its impact in Canada is still within the expected range. Influenza seasons vary in severity and generally result in more cases when an influenza A H3N2 virus is circulating, as is the case this year. A/Fujian, a new strain of H3N2 (a type of influenza A) has been documented in many countries, including Canada.

On average, 500-1500 deaths per year are reported in Canada due to influenza or pneumonia as a complication of influenza. In addition, many more deaths may occur in people with underlying medical conditions complicated by influenza. Since the start of the current influenza season, Health Canada has reported two deaths in children with confirmed influenza A infection, and two other child deaths that are suspected to be the result of influenza, but this has not been confirmed.

While Tamiflu has been demonstrated to be effective and well tolerated in treating patients as young as 1-year-old, preclinical findings in juvenile rats have raised possible concerns regarding the use of Tamiflu in infants less than 1 year of age. A single dose of 1000 mg/kg oseltamivir phosphate (about 250 times the recommended dose in children) in 7-day-old rats resulted in deaths associated with unusually high exposure to both oseltamivir and oseltamivir phosphate (refer to TAMIFLU Product Monograph: Toxicology/Multiple Dose Toxicity section). Further studies showed levels of oseltamivir phosphate in the brain to be approximately 1500 times those seen in adult animals. It is likely that these high exposures are related to an immature blood-brain barrier. Studies showed no deaths or other significant effects in older juvenile rats given the same or higher doses of Tamiflu. The exposures to oseltamivir phosphate associated with no adverse effects in the brain of juvenile rats correspond to approximately 800-fold the exposure expected in a 1-year-old child. The clinical significance of these preclinical data to human infants is uncertain. However, given the uncertainty in predicting the exposures in infants with immature blood-brain barriers, it is recommended that Tamiflu not be administered to children younger than 1 year, the age at which the human blood-brain barrier is generally recognized to be fully developed.

Due to the significance of this information the Product Monograph will be revised to include these preclinical findings. Given the possible desire to treat very young children with Tamiflu during this active influenza season, we wish at this time to emphasize the importance of using Tamiflu only for labeled indications and only in patients 1 year and older.

The identification, characterization, and management of marketed health product-related adverse events are dependent on the active participation of Healthcare Professionals in adverse event reporting programs. Healthcare Professionals are asked to report any suspected adverse events in patients receiving Tamiflu (oseltamivir phosphate) to Hoffman-La Roche Ltd. at the following address:

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 use of drugs.

Should you have any questions or require additional information regarding the use of Tamiflu (oseltamivir phosphate), please contact the Drug Information and Safety Department at Hoffmann-La Roche Limited at 1-888-762-4388 from 9 a.m. to 5 p.m. Monday to Friday Eastern Standard Time.

Sincerely,

original signed by

Lorenzo Biondi,
Vice President, Medical and Regulatory Affairs