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This application is a service of the Singapore Government.

Health Sciences Authority

27 Dec 2017: Risk of hepatitis B virus reactivation with ibrutinib

HSA would like to bring to the attention of healthcare professionals the potential risk of hepatitis B virus (HBV) reactivation associated with ibrutinib treatment. This risk was identified by the European Medicines Agency (EMA) following its review of overseas cases of HBV reactivation in patients who received treatment with ibrutinib.

Ibrutinib (Imbruvica®, Johnson & Johnson Pte Ltd), registered locally in July 2015, is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). It is approved for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, chronic lymphocytic leukaemia (CLL), including CLL with 17p deletion, and Waldenström’s macroglobulinaemia.

BTK is an important signalling molecule of the B-cell antigen receptor (BCR) pathway implicated in the pathogenesis of several B-cell malignancies, including MCL and B-cell CLL. The inhibition of BTK by ibrutinib blocks BCR signalling, thus interfering with malignant B-cell proliferation and survival.

Review by the EMA1, 2

The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) conducted a routine review examining the safety profile of ibrutinib, which identified cases of HBV reactivation in ibrutinib-treated patients. This cumulative review took into consideration available data from clinical trials, scientific literature, as well as postmarketing adverse drug reaction reports of HBV reactivation in patients receiving ibrutinib treatment.

EMA’s review of cumulative data available till November 2016 identified eight cases of HBV reactivation in which the role of ibrutinib was considered possible or probable. In other cases, the role of ibrutinib in the onset of HBV reactivation could not be clearly established due to confounding by prior or concomitant treatment regimens known to be associated with the development of viral reactivation. The remaining cases had insufficient information to allow for meaningful causality assessment. None of the cases of HBV reactivation had led to fulminant liver failure requiring liver transplantation. However, there was one report with a fatal outcome, which was attributed to HBV reactivation and concurrent metastatic melanoma of the liver, lung and spleen.

Based on review of the available information, the EMA’s PRAC concluded in June 2017 that the benefit-risk balance of ibrutinib in relation to its approved indications remained unchanged. However, the PRAC recommended that healthcare professionals establish the HBV status of patients prior to initiating treatment with ibrutinib. In patients with positive hepatitis B serology, consultation with a hepatic disease expert is recommended before initiating treatment with ibrutinib. The PRAC also advised that patients with positive hepatitis B serology who require ibrutinib be monitored and managed according to local medical standards of care, so as to minimise the risk of HBV reactivation. A letter to healthcare professionals was issued across the European Union (EU) in July 2017 to inform them about this new safety information. The EU product information for ibrutinib would also be updated to include warnings on the risk of HBV reactivation and to include HBV reactivation as an uncommon adverse reaction.

Local situation and HSA’s advisory

To date, HSA has not received any local adverse reaction report of HBV reactivation in patients receiving treatment with ibrutinib. Johnson & Johnson Pte Ltd has informed HSA that the Singapore package insert for Imbruvica® will be updated to include safety information regarding the risk of HBV reactivation. In view of the higher prevalence of hepatitis B in Singapore than in Europe, and the potentially serious outcomes caused by HBV reactivation in immunosuppressed patients, healthcare professionals should ensure that HBV status is established before initiating treatment with ibrutinib. They are also advised to closely monitor patients with positive hepatitis B serology who require ibrutinib and institute appropriate therapy as indicated to minimise the risk of hepatitis B reactivation.