March 1999

Important Prescribing Information:
Potential Xeloda Interaction with Coumarin Derivatives

The Drug Safety Department of Hoffman-La Roche has received reports of altered coagulation parameters and/or bleeding in cancer patients on Xeloda (capecitabine) who were taking coumarin derivatives concomitantly. The time of occurrence of these events (altered coagulation parameters and/or bleeding) ranged from several days to several months after starting Xeloda therapy and in isolated cases, occurred within one month after the last dose of Xeloda. The mechanism of action whereby Xeloda might alter coagulation parameters is unclear and will be further investigated. Apart from the known difficulties of sustaining stable INR's in cancer patients, there may have been confounding variable underlying the alterations in coagulation such as trauma, dietary changes or inconsistencies, hepatic dysfunction, hypermetabolic states, and concomitant use of other agents that have the potential to interact with coumarin derivatives.

After discussion and review of these reports with the FDA, we feel at this time that an effect of Xeloda on coagulation parameters in patients taking concomitant warfarin or related coumarin derivative anticoagulants cannot be ruled out. However, because of the potential clinical significance of such an interaction, Hoffman-La Roche recommends that patients taking Xeloda with concomitant coumarin derivatives should be monitored regularly for alterations in their coagulation parameters (PT or INR). If your patient's anticoagulant therapy is being prescribed and/or monitored by another physician, please inform them of the above information.

Please note that the following new information has been added to two sections of the package insert. These include:

WARNINGS:
General:
Coagulopathy: Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. The events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within one month after stopping capecitabine. These events occurred in-patients with and without liver metastases. Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or INR).

PRECAUTIONS:
Drug-Drug Interactions: Interaction with coumarin anticoagulants: Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or INR).

The medical community can further our understanding of these events by reporting all cases to Hoffman-La Roche at 1-800-526-6367 or the FDA MedWatch program by phone at 1-800-FDA-1088, by Fax 1-800-FDA-1078 or by mail: MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857.

The new package insert is enclosed for your information. If you have any questions, please call Roche Professional Product Information at 1-800-526-6367.

Sincerely,

Fabio Benedetti, M.D.
Medical Director