October 12, 2016 – This is a communication from Health Canada, issued in May 2016, concerning the danger of reactivation of hepatitis B virus (HBV) infection in patients treated with BCR-ABL tyrosine kinase inhibitors (TKIs) and geared towards healthcare professionals (medical oncologists, hematologists, gastroenterologists, oncology nurses, pharmacists), pharmacy associations, medical associations, chiefs of medicine in hospitals, hospital pharmacy chiefs), patients, and patient groups. Reactivation of hepatitis B virus (HBV) infection with direct-acting antivirals (DAA) for hepatitis C virus (HCV)-infection has been the issue of a very recent drug safety communication by the FDA and was covered by thasso post too. At present time, it is not known by which mechanism(s) classes of drugs as diverse as BCR-ABL TKI’s and DAA’s could lead to the reactivation of HBV-infections in patients treated for equally diverse indications such as hematological malignancies and HCV-infection, respectively.
The key messages of the present communication are:
- Cases of reactivation of hepatitis B virus (HBV) have occurred in patients who are chronic carriers of HBV after they received BCR-ABL tyrosine kinase inhibitors (TKIs). Some cases of HBV reactivation resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
- It is recommended that:
- Patients be tested for HBV infection before initiating treatment with BCR-ABL TKIs.
- Experts in liver disease and in the treatment of HBV be consulted promptly before initiating treatment in chronic HBV carriers (including those with active disease) and in patients who test positive for HBV infection during treatment.
- Patients who are carriers of HBV requiring treatment with BCR-ABL TKIs be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
- The Canadian prescribing and consumer information for BCR-ABL TKIs will be updated to reflect this new safety information.
The central issue behind this communication was a recent review of data from clinical trials and postmarketing experience showing that HBV reactivation can occur in chronic HBV carriers, after they received BCR-ABL TKIs. Some of these cases included acute hepatic failure or fulminant hepatitis leading to liver transplantation or death. These case reports indicate that HBV reactivation may occur at any time during BCR-ABL TKI treatment. Some of these patients had a documented history of hepatitis B. An increase in viral load or positive serology after initiating treatment with a BCR-ABL TKI occurred with HBV reactivation. For other cases, the serologic status at baseline was not known. HBV reactivation is considered to be a class-effect of BCR-ABL TKIs, although the mechanism and the frequency of HBV reactivation during exposure is not known at this time.
|Brand Name||Active ingredient||Manufacturer|
|GLEEVEC||imatinib mesylate||Novartis Pharmaceuticals Canada Inc.|
|TASIGNA||nilotinib||Novartis Pharmaceuticals Canada Inc.|
|BOSULIF||bosutinib||Pfizer Canada Inc.|
|SPRYCEL||dasatinib||Bristol-Myers Squibb Canada|
|ICLUSIG||ponatinib hydrochloride||ARIAD Pharmaceuticals, Inc.|
Who is affected?
Information for consumers: Talk to your doctor, pharmacist or nurse before taking GLEEVEC (imatinib mesylate), SPRYCEL (dasatinib), TASIGNA (nilotinib), BOSULIF (bosutinib), or ICLUSIG (ponatinib hydrochloride) and let them know if you have ever had or might now have a hepatitis B or liver infection. This is because these drugs could cause hepatitis B virus to become active again, which can be fatal in some cases. Signs and symptoms of hepatitis include: weight loss, fever, abdominal pain, nausea and vomiting followed by yellowing of the skin (jaundice). It is important to be carefully checked by your doctor for signs of this infection before treatment is started.
Information for health care professionals: Patients should be tested for HBV infection status before initiating treatment with BCR-ABL TKIs. Healthcare professionals should consult experts in liver disease and in the treatment of HBV promptly before starting treatment with BCR-ABL TKIs in patients with positive HBV serology (including those with active disease) and in patients who test positive for HBV infection during treatment. Healthcare professionals should closely monitor patients who are carriers of HBV, who are currently on or require a BCR-ABL TKI treatment for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. The Canadian Product Monographs will be updated to reflect this new safety information.
Action taken by Health Canada: Health Canada, in collaboration with the appropriate manufacturers including manufacturers of generic versions (see “Products affected”) will update the Canadian prescribing and consumer information.