December 5, 1998

It is important that Genentech, Inc. and IDEC Pharmaceuticals Corporation inform you of eight post-marketing reports of severe infusion-related adverse events associated with the use of RITUXAN (rituximab) that resulted in fatal outcomes. These adverse events represent an increase in the severity of infusion-related symptoms. Since its approval in November 1997, for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma, approximately 70 cases of serious infusion-related events have been reported out of an estimated 12,000 to 14,000 patients that have been treated with rituximab worldwide. The labeling for RITUXAN (rituximab) will be revised to reflect this new information.

In seven of the eight fatalities, severe symptoms occurred during the first RITUXAN (rituximab) infusion. The cause of death was not reported or remains unknown for two of the eight cases. In most cases, death was preceded by severe bronchospasm, dyspnea, hypotension, and/or angioedema. Severe respiratory events, including hypoxia, pulmonary infiltrates, and adult respiratory distress syndrome, contributed to six of the eight reported deaths. In some cases symptoms worsened over time, while in others initial improvement was followed by clinical deterioration. Therefore, patients experiencing any of the severe infusion-related symptoms mentioned above or in the labeling (see ADVERSE REACTIONS section of the enclosed package insert) should be monitored closely until complete resolution of their symptoms occurs.

Review of the reports for these eight patients did not reveal a common pattern of predisposing factors. However, it appears that patients with a high tumor burden or with a high number (>50,000/mm³) of circulating malignant cells may be at higher risk. Therefore, these patients should be treated with extreme caution and be closely monitored throughout each infusion. The package insert was revised in September 1998 to include additional information in the WARNINGS section regarding tumor lysis syndrome and the management of patients presenting with tumor lysis syndrome.

Please consult the WARNINGS section of the enclosed RITUXAN (rituximab) package insert for information on monitoring and handling patients experiencing hypersensitivity reactions or other infusion-related symptoms.

This new safety information will help in the management of your lymphoma patients who receive RITUXAN (rituximab) therapy. Should you have any questions regarding the use of RITUXAN (rituximab), please call our Medical Information Department at 1-800-821-8590.

Healthcare professionals should report any serious adverse events suspected to be associated with the use of RITUXAN (rituximab) to Genentech at 1-8000-626-3553, extension 57541. Alternatively, this information may also be reported to FDA's MedWatch reporting system by phone (1-800-FDA-1088), facsimile (1-800-FDA-0178), or mailed to MedWatch using form FDA 3500 to HF-2 5600 Fishers Lane, Rockville, MD 20852-9787.

Sincerely,

Susan D. Hellmann, MD, MPH
Senior Vice President
Chief Medical Officer
Genentech, Inc.
1 DNA Way
South San Francisco, CA 94080-4990
650-225-1000

Antonio J. Grillo-Lopez, M.D.
Senior Vice President
Medical and Regulatory Affairs
IDEC Pharmaceuticals Corporation
11011 Torreya Road
San Diego, CA 92121
619-850-8500

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