Rituximab (Mabthera®, Roche) is a recombinant chimeric anti-CD20 monoclonal antibody licensed in Singapore for: i) treatment of patients with relapsed or chemo-resistant indolent B-cell non-Hodgkin's lymphomas (NHL), ii) treatment of patients with CD20 positive diffuse large B-cell non-Hodgkin's lymphomas (DLCL) in combination with CHOP* therapy, iii) treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with CVP** chemotherapy.
In the past few months, there have been reports of hepatic failure, bowel obstruction and perforation, and progressive multifocal leukoencephalopathy (PML) suspected to be associated with its use. The causality of some of these adverse events has not been established although its immunosuppressant effects may account for PML.
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In November 2006, Health Canada together with Hoffmann-La Roche in Canada issued an advisory to healthcare professionals about the observation of bowel obstruction and gastrointestinal perforations in patients treated with rituximab.
The advisory included data from the analysis of the company's worldwide pharmacovigilance database for rituximab which indicated that 47 cases of bowel obstruction (nine deaths) and 37 cases of gastrointestinal perforation (four deaths) have been reported in rituximab patients for an estimated 730,000 cumulative patient exposure. These reports originated from both spontaneous sources and clinical studies, and the majority of these cases were reported for the NHL indication. Of these, two reports of bowel obstruction (one death) and two reports of gastrointestinal perforation originated from Canada.
The advisory also mentioned that the presence of risk factors such as underlying medical history (e.g. gastrointestinal lymphoma) and intake of concomitant medications (e.g. chemotherapy and steroids) in the cases of bowel obstruction and gastrointestinal perforation made interpretation of data difficult. However these confounding factors, a contributory role of rituximab in causing gastrointestinal perforation in patients diagnosed with NHL has not been excluded. In addition, a pooled analysis of clinical trials in patients with NHL has indicated a higher incidence of gastrointestinal perforation in the arms treated with rituximab/chemotherapy compared to the arms treated with chemotherapy alone (0.38% versus 0.15%).
In post-marketing reports of patients with NHL, the mean time to onset of symptoms was six days from the start of therapy (range 1 to 77 days) for documented gastrointestinal perforation. The site of gastrointestinal perforation in the cases of NHL included both the upper and lower gastrointestinal tracts.
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b) New reports of fulminant hepatitis in Hepatitis B virus carriers
The Ministry of Health, Labour and Welfare of Japan has in December 2006, requested the product licence holder to disseminate a dear healthcare professional letter and to strengthen the package insert of rituximab to warn of cases of fatal liver failure caused by fulminant hepatitis or exacerbation of hepatitis in hepatitis B virus carrier treated with rituximab (marketed as Mabthera® in Japan).
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The US Food and Drug Administration has also in December 2006 alerted healthcare professionals of two fatal cases of progressive PML in patients treated with rituximab (marketed as Rituxan® in US) for systemic lupus erythematosus (SLE) which was not an approved indication of the drug. PML is a demyelinating disease caused by reactivated JC virus which is a latent virus present in 80% of adults.
Reactivation or exacerbation of viral infections including JC virus leading to PML may occur when patients receive Rituxan® for any reason. To date, there are 23 confirmed reports of PML in patients with lymphoid malignancies treated with rituximab although PML has also been reported in SLE patients not treated with rituximab.
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Local situation
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References
- Health Canada Advisory for Healthcare Professionals (10/11/06)
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2006/rituxan_3_hpc-cps_e.html - US FDA information for Healthcare Professionals (18/12/06)
http://www.fda.gov/cder/drug/infopage/rituximab/default.htm - US FDA Public Health Advisory (18/12/06) http://www.fda.gov/cder/drug/advisory/rituximab.htm
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** CVP - vincristine, cyclophosphamide, prednisolone
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