FDA Drug Safety Communication: Boxed Warning and new recommendations to decrease risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab)

This is a very important notice from the Food and Drug Administration about possible re-activation of hepatitis B when using immunosuppressive drugs (Arzerra (ofatumumab) and Rituxam (rituximab). Everyone should be screened for HBV before using these drugs due to reactivation and possible severe disease progression and death. Many patients and medical providers are confused about hepatitis B infection status—resolved and chronic. Be sure to tell your medical provider of a previous hepatitis B infection and also request a test to find out your current HBV status. As you can see by the information below, there is a real possibility of serious health consequences if a person’s status is not monitored. –Alan Franciscus

Safety Announcement
[9-25-2013] The U.S. Food and Drug Administration (FDA) has approved changes to the prescribing information of the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab) to add new Boxed Warning information about the risk of reactivation of hepatitis B virus (HBV) infection.  The revised labels also will include additional recommendations for screening, monitoring, and managing patients on these drugs to decrease this risk.  Both Arzerra and Rituxan are used to treat certain cancers of the blood and lymph system. Rituxan is also approved to treat other medical conditions, including rheumatoid arthritis. Both drugs suppress the body’s immune system.

In patients with prior HBV infection, HBV reactivation may occur when the body’s immune system is impaired.  This infection can cause serious liver problems, including liver failure and death. 

Reactivation can occur in patients who previously had HBV infection that was clinically resolved, but who later require therapy for a condition such as cancer.  When a treatment is given that can impair the body’s immune system, the previous HBV infection can again become an active infection.  The initial HBV infection may occur without obvious signs of liver disease, and it may remain dormant in liver tissue.  Therefore, screening for evidence of prior exposure is necessary to reliably assess the risk of HBV reactivation.

The risk of HBV reactivation is already described in the Warnings and Precautions section of the labels for both drugs; however, cases continue to occur, including deaths, prompting FDA to examine this risk further for current evidence that may aid in recognition and reduction in the risk (see Data Summary). HBV reactivation is being added to the existing Boxed Warning of the Rituxan label, and a new Boxed Warning is being created for the Arzerra label to describe the risk. The Warnings and Precautions section also is being revised for each drug to express new recommendations.

To decrease the risk of HBV reactivation, we recommend that health care professionals:
Health care professionals and patients should discuss the risks of serious infections, including HBV, before starting treatment with Arzerra or Rituxan. Patients should talk to their health care professional if they have any questions or concerns about these drugs.

Facts about Arzerra (ofatumumab) and Rituxan (rituximab)

Additional Information for Patients
Additional Information for Health Care Professionals
Data Summary
FDA searched its Adverse Event Reporting System (AERS) database for reports submitted between the time of market approval of the drugs (November 1997 for Rituxan; October 2009 for Arzerra) and August 2012 of patients treated with Arzerra (ofatumumab) or Rituxan (rituximab) who had fatal hepatitis B-related acute liver injury.

The search identified 109 cases (Rituxan=106; Arzerra=3). Acute liver injury was attributed to hepatitis B virus (HBV) reactivation when the case data indicated an associated seroconversion of hepatitis B surface antigen (HBsAg) from negative to positive for those with either hepatitis B core antibody (anti-HBc) or a history of HBV, or the case reported an increase in HBV DNA level among those who were HBsAg positive before Arzerra or Rituxan treatment.

Of the 109 cases, 32 (Rituxan=31; Arzerra=1) contained sufficient data in the reports to meet the HBV reactivation criteria.  HBsAg seroconversion was the basis of diagnosis for 69% (22/32) of cases.  Nineteen of 22 cases that were HBsAg negative prior to initiation of Arzerra or Rituxan therapy were positive for anti-HBc (5 of the 22 cases were also hepatitis B surface antibody [anti-HBs] positive).  No case had anti-HBs antibody alone. The remaining cases were HBsAg positive and diagnosed by an increase in HBV DNA level.  Of the 32 cases, 10% (3/32) were on HBV antiviral prophylaxis and 28% (9/32) reported receiving antiviral treatment for HBV reactivation.  The mean age of the patients was 62 years (range 27-84 years), and most were male (n=21); one case did not provide the age or sex.  Duration of Arzerra or Rituxan therapy prior to HBV reactivation diagnosis was highly variable with a range of 63 days from the first dose to 12 months from the last dose.  All cases had recent or concomitant exposure to other chemotherapy agents also.

Among the 77 patients who did not include the required data for the HBV reactivation criteria, 47% (36/77) had no documented screening and 32% (25/77) reported partial screening.  The remaining 21% had insufficient information to distinguish reactivation from primary hepatitis B (8/77) or were from literature reports without validation (8/77).

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