FDA Issues a New Black Box Warning for CD20-Directed Monoclonal Antibodies

The FDA has added a new black box warning to 2 drugs, rituximab (Rituxan) and ofatumumab (Arzerra) for the potential of either drug to cause reactivation of hepatitis B virus (HBV) as well as fulminant and fatal HBV infection in HBV carriers who have not had any prior instances of HBV virus activation.

Ofatumumab, originally approved in 2009, is an injectable CD20-directed cytolytic monoclonal antibody indicated for refractory cases of chronic lymphocytic leukemia (CLL). Like ofatumumab, rituximab is a CD20-directed cytolytic antibody. Initially approved in 1997, rituximab has several indications for treatment of non-Hodgkin’s lymphoma and CLL. Rituximab may also be part of a regimen for treatment of rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis. In September 2011, the "Warnings and Precautions" section of both the rituximab and the ofatumumab package inserts were updated to include a warning for potential reactivation of HBV.

The new black box warning contains recommendations for screening of patients receiving ofatumumab or rituximab for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating treatment. Even after cessation of therapy, the new warning recommends monitoring for reactivation, as reactivation of HBV has occurred in some patients several months after completion of therapy.

The black box warning is an escalation of prior warnings. For instance, in 2004, Genentech and Biogen Idec jointly sent a letter to health care professionals regarding updates to the rituximab package insert regarding the potential for HBV reactivation following case reports of fulminant hepatitis, hepatic failure, and death in patients with hematologic malignancies who received rituximab.

A 2011 meta-analysis of rituximab-associated reactivations of HBV identified 183 cases of HBV exacerbations after treatment. Time to reactivation ranged from 0 to 12 months and occurred an average of 3 months after treatment. However, 29% of cases occurred more than 6 months after cessation of treatment.

The recent labeling revisions will strengthen awareness of important monitoring parameters among health care professionals prescribing ofatumumab or rituximab.