Bendamustine (Levact): increased mortality observed in recent clinical studies in off-label use; monitor for opportunistic infections, hepatitis B reactivation

Recent clinical trials have shown increased mortality when bendamustine (Levact) was used in combination treatments outside its approved indications. Be aware that the risk of opportunistic infections for all patients receiving bendamustine including those receiving off-label treatment may be greater than previously recognised. Be aware of your responsibilities if prescribing bendamustine outside the licensed indications.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 20 July 2017

• Therapeutic area: Cancer, Haematology, Infectious disease

Advice for healthcare professionals:

• advise patients to report promptly new signs of infection, including fever or respiratory symptoms, and consider discontinuing bendamustine if there are signs of opportunistic infections
• monitor patients for opportunistic infections as well as cardiac, neurological, and respiratory adverse events
• hepatitis B virus (HBV) reactivation has also been reported; monitor known carriers of HBV for signs and symptoms of active HBV infection
• increased mortality (mainly due to opportunistic infections) was observed in recent clinical studies when bendamustine was used in combination treatment outside the approved indications
• report suspected adverse reactions associated with bendamustine to us on a Yellow Card

Background

Bendamustine is indicated for:

• first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate

• indolent non-Hodgkin’s lymphomas as monotherapy in patients, who have progressed during or within 6 months following treatment with rituximab or a rituximab-containing regimen

• front-line treatment of multiple myeloma (Durie-Salmon stage II with progression or stage III) in combination with prednisone for patients older than 65 years who are not eligible for autologous stem cell transplantation and who have clinical neuropathy at the time of diagnosis limiting the use of thalidomide or bortezomib-containing treatment

Recent clinical trial findings

In clinical trials^{[footnote 1] [footnote 2]} of non-approved combination therapies, bendamustine was associated with increased mortality and an unfavourable safety profile when used in combination with rituximab or obinutuzumab.

Deaths were mainly due to infections including bacterial (sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia, varicella zoster virus, and cytomegalovirus infection. Some fatal cardiac, neurological, and respiratory toxicities were also reported.

Post-marketing data

Opportunistic infections

A recent European review of post-marketing data has suggested that the risk of opportunistic infections with bendamustine treatment may be greater than previously recognised.

Consult the revised summary for product characteristics and be aware of updated warnings regarding infections.

Infections include bacterial (sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia, varicella zoster virus, and cytomegalovirus infection.

Both the frequency and outcome of infections seem to be highly variable and dependent on the clinical setting. High frequencies of opportunistic infections may be linked to lymphocytopenia and low CD4-positive T-cell counts. Lymphocytopenia (<600 cells per µL) and low CD4-positive T-cell counts (<200 cells per µL) lasting at least 7–9 months after treatment with bendamustine has been reported in a significant portion of patients. Lymphocytopenia and CD4-positive T-cell depletion are thought to be more pronounced when bendamustine is combined with rituximab.

You should:

• monitor patients for respiratory signs and symptoms throughout treatment

• advise patients to report new signs of infection, including fever or respiratory symptoms promptly

• consider discontinuing bendamustine if there are signs of opportunistic infections

Hepatitis B virus reactivation

Reactivation of hepatitis B virus in chronic carriers of the virus has been reported after bendamustine. Some cases resulted in acute hepatic failure or a fatal outcome. Closely monitor carriers of hepatitis B virus for signs and symptoms of active infection.

Prescribing off-label or unlicensed medicines

Refer to prescribers’ responsibilities for off-label or unlicensed use of medicines.

Reporting of suspected adverse reactions

Suspected adverse reactions should be reported to us on a Yellow Card including those associated with use outside the licence.

Further information

Letter sent to healthcare professionals

Levact (bendamustine), summary of product characteristics

Article citation: Drug Safety Update volume 10 issue 11, July 2017: 2.

1. Flinn IW, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014; 123: 2944–52. ↩

2. Sehn LH, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016; 17: 1081–93. ↩

Published 20 July 2017