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:
-
Consult with hepatitis
experts regarding monitoring and use of HBV antiviral therapy when
screening identifies patients at risk of HBV reactivation due to
evidence of prior HBV infection.
-
Monitor patients with
evidence of prior HBV infection for clinical and laboratory signs of
hepatitis B or HBV reactivation during Arzerra or Rituxan therapy and
for several months thereafter, since reactivations have occurred
several months following completion of therapy with these drugs.
-
In patients who develop
reactivation of HBV while on Arzerra or Rituxan, immediately
discontinue the drug and start appropriate treatment for HBV. Also
discontinue any chemotherapy the patient is receiving until the HBV
infection is controlled or resolved. Because of insufficient data, no
recommendation can be made regarding the resumption of Arzerra or
Rituxan in patients who develop HBV reactivation hepatitis.
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)
- Arzerra and Rituxan are in a class of drugs called anti-CD20-directed monoclonal antibodies.
- Arzerra is used to treat chronic lymphocytic
leukemia (CLL) in patients who have further disease after treatment with
the anti-cancer drugs fludarabine and alemtuzumab.
- Rituxan is used to treat non-Hodgkin’s lymphoma
and CLL. It is also used to treat other medical conditions,
including rheumatoid arthritis, granulomatosis with polyangiitis, and
microscopic polyangiitis.
Additional Information for Patients
- If you have had hepatitis B or are a carrier of
hepatitis B virus (HBV), receiving Arzerra (ofatumumab) or Rituxan
(rituximab) could cause the virus to become an active infection
again. HBV reactivation may cause serious liver problems, including
liver failure and death.
- Before receiving Arzerra or Rituxan, tell your
health care professional if you have or have had any severe
infections, including HBV.
- If you have had HBV infection, your health care
professional should monitor you for HBV infection during treatment and
for several months after you stop treatment with Arzerra or Rituxan.
- Talk to your health care professional if you have any questions or concerns about Arzerra or Rituxan.
- Report side effects from Arzerra or Rituxan to
the FDA MedWatch program, using the information in the "Contact FDA"
box at the bottom of this page.
Additional Information for Health Care Professionals
- Hepatitis B virus (HBV) reactivation has
occurred in patients with prior HBV exposure who are later treated
with drugs classified as CD20-directed cytolytic antibodies, including
Arzerra (ofatumumab) and Rituxan (rituximab). Some cases have
resulted in fulminant hepatitis, hepatic failure, and death.
- HBV reactivation is defined as an abrupt
increase in HBV replication manifesting as a rapid increase in serum
HBV DNA level or detection of HBsAg in a person who was previously
HBsAg negative and anti-HBc positive. Reactivation of HBV replication
is often followed by hepatitis (i.e., increase in transaminase levels
and, in severe cases, increase in bilirubin levels, liver failure, and
death).
- Cases of HBV reactivation have been reported in patients who are hepatitis B surface antigen (HBsAg) positive.
- Cases have also been reported in patients who
are HBsAg negative, but test positive for hepatitis B core antibody
(anti-HBc). Reactivation also has occurred in patients who appear to
have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc
positive, and hepatitis B surface antibody [anti-HBs] positive).
- Screen all patients for HBV infection before initiating treatment with Arzerra or Rituxan by measuring HBsAg and anti-HBc.
- Note that patients who have protective antibodies due to immunization will test positive only for anti-HBs.
- For patients who show evidence of prior HBV
exposure by testing positive for HBsAg or anti-HBc, consult with
physicians with expertise in managing hepatitis B regarding monitoring
and consideration for HBV antiviral therapy.
- Monitor patients with evidence of prior HBV
infection for clinical and laboratory signs of hepatitis or HBV
reactivation during and for several months following Arzerra or Rituxan
therapy. HBV reactivation has been reported up to 12 months following
completion of therapy.
- In patients who develop reactivation of HBV
while on Arzerra or Rituxan, immediately discontinue the drug and
institute appropriate HBV treatment. Also discontinue any concomitant
chemotherapy the patient is receiving until the HBV infection is
controlled or resolved. Because of insufficient data, no
recommendation can be made regarding the resumption of Arzerra or
Rituxan in patients who develop HBV reactivation hepatitis.
- Report adverse events involving Arzerra or
Rituxan to the FDA MedWatch program, using the information in the
"Contact FDA" box at the bottom of this page.
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).
Contact FDA:
1-800-332-1088
1-800-FDA-0178 Fax
Labels: Arzerra, FDA Warning, reactivation, Rituxan