Archived – Possible Association of RITUXAN (Rituximab) with Hepatitis B Reactivation – Hoffmann-La Roche Limited

Starting date:

July 27, 2004

Posting date:

July 30, 2004

Type of communication:

Dear Healthcare Professional Letter

Subcategory:

Biologic/vaccine

Source of recall:

Health Canada

Issue:

Important Safety Information

Audience:

Healthcare Professionals

Identification number:

RA-17000815

This is duplicated text of a letter from Hoffmann-La Roche Limited.

Contact the company for a copy of any references, attachments or enclosures.

Notice about Health Canada advisories

Health Canada Endorsed Important Safety Information on RITUXAN (rituximab)

July 27, 2004

Subject: Possible Association of RITUXAN^® (rituximab) with Hepatitis B Reactivation

Dear Health Care Professional,

Hoffmann-La Roche Limited, following discussions with Health Canada, would like to inform you of new safety data that have implications for the use of RITUXAN (rituximab).

RITUXAN is indicated for the treatment of patients with relapsed or refractory low grade or follicular, CD20 positive, B cell non Hodgkin's lymphoma and patients with CD20 positive, diffuse large B-cell non-Hodgkin's lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. It is estimated that over half a million treatments have been administered worldwide. Since RITUXAN was introduced to the market, Hoffmann-La Roche Limited has continued to gather information on the safety and efficacy of RITUXAN.

Based upon review of recent post marketing and clinical safety reports:

• Hepatitis B virus (HBV) reactivation, occasionally with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignancies treated with RITUXAN, mostly in combination with chemotherapy.
• Persons at high risk of HBV infection should be screened before initiation of RITUXAN.
• Carriers of hepatitis B and patients with evidence of having recovered from hepatitis B infection should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and up to one year following RITUXAN therapy.

Very rare cases (less than 1 adverse event per 10000 treated patients) of Hepatitis B reactivation in association with RITUXAN therapy were reported internationally, of which 1 report involved a Canadian patient. The majority of patients received RITUXAN in combination with chemotherapy. Isolated cases have been reported in patients who either had evidence of antibodies against Hepatitis B surface antigen before treatment or did not have any such antibodies. Reporting rates determined on the basis of spontaneously reported post-marketing adverse events are generally presumed to underestimate the risks associated with drug treatments. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of RITUXAN and approximately one month after the last dose.

Persons at high risk of HBV infection should be screened before initiation of RITUXAN. Reactivation of Hepatitis B virus (HBV) infection is a well-known complication in patients with chronic hepatitis B, especially in those receiving cytotoxic or immunosuppressive therapy. In addition, non-Hodgkin's lymphoma (NHL) of itself may be an independent risk factor for HBV reactivation. Carriers of hepatitis B, and patients with evidence of having recovered from hepatitis B infection, should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and up to one year following RITUXAN therapy.

In patients who develop reactivation of viral hepatitis B, RITUXAN and any concomitant chemotherapy should be discontinued and appropriate treatment including antiviral therapy initiated. There are insufficient data regarding the safety of resuming RITUXAN therapy in patients who develop hepatitis subsequent to HBV reactivation.

Due to the nature of this information, the Product Monograph will be revised to include these findings. The identification, characterization, and management of marketed health product-related adverse events are dependent on the active participation of health care professionals in adverse reaction reporting programs. Any occurrences of hepatitis B reactivation or other serious and/or unexpected adverse reactions in patients receiving RITUXAN should be reported to Hoffmann-La Roche Ltd. or Health Canada at the following addresses:

Hoffmann-La Roche Limited

Drug Information and Safety Department

2455 Meadowpine Boulevard

Mississauga, Ontario, L5N 6L7

or call toll free at: 1-888-762-4388

or Fax at: 905-542-5610

or email to: mississauga.canada_medinfo@roche.com

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

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.

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 RITUXAN (rituximab), please contact the Drug Information and Safety Department at Hoffmann-La Roche Limited at 1-888-762-4388 from 8:30 a.m. to 4:30 p.m. Monday to Friday Eastern Standard Time.

Sincerely,

original signed by

Lorenzo Biondi

Vice President,

Medical and Regulatory Affairs

References:

1. Westhoff TH, Jochimsen F, Schimittel A, Stoffler-Meilchke M, Schafer JH, Zidek W, et al. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood 2003;102(5):1930.
2. Hernandez-Jose A, Diloy R, Salat D, del-Rio N, Martinez X, Castellvi-Josep M. Fulminant hepatitis subsequent to reactivation of precore mutant hepatitis B virus in a patient with lymphoma treated with chemotherapy and rituximab. Haematologica 2003;88(6):ECR22.
3. Ng HJ, Lim LC. Fulminant hepatitis B virus reactivation with concomitant listeriosis after fludarabine and rituximab therapy: case report. Ann Hematol 2001;80:549-552.
4. Dervitte I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who has receiving rituximab. N Engl J Med 2001;344(1):68-69.
5. Tsutsumi Y, Kawamura T, Saitoh S, Yamada M, Obara S, Miura T, et al. Hepatitis B virus reactivation in a case of non-Hodgkin's lymphoma treated with chemotherapy and rituximab: necessity of prophylaxis for hepatitis B virus reactivation in rituximab therapy. Leukemia and Lymphoma 2004;45(3):627-629.
6. Kami M, Hamaki T, Murashige N, Kishi Y, Kusumi E, Yuji K, et al. Safety of rituximab in lymphoma patients with hepatitis B or hepatitis C virus infection. Hematology Journal 2003;4(2):159-162.