Bendamustine Kabi Special Precautions

Myelosuppression: Patients treated with bendamustine may experience myelosuppression. In the event of treatment-related myelosuppression, leukocytes, platelets, haemoglobin, and neutrophils must be monitored at least weekly. Prior to the initiation of the next cycle of therapy, the following parameters are recommended: Leukocyte and/or platelet values > 4,000/µl or > 100,000/µl, respectively.
Secondary malignancies: Malignancies (including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial cancer) and premalignant disease have been reported in patients who have received bendamustine.
Infections: Serious and fatal infections have occurred with bendamustine, including bacterial (sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), varicella zoster virus (VZV) and cytomegalovirus (CMV). Treatment with bendamustine may cause prolonged lymphocytopenia (< 600/µl) and low CD4-positive T-cell (T-helper cell) counts (< 200/µl) for at least 7-9 months after the completion of treatment. Lymphocytopenia and CD4-positive T-cell depletion are more pronounced when bendamustine is combined with rituximab. Patients with lymphopenia and low CD4-positive T-cell count following treatment with bendamustine are more susceptible to (opportunistic) infections. In case of low CD4-positive T-cell counts (< 200/µl) Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be considered. All patients should be monitored for respiratory signs and symptoms throughout treatment. Patients should be advised to report new signs of infection, including fever or respiratory symptoms promptly. Discontinuation of bendamustine should be considered if there are signs of (opportunistic) infections.
Hepatitis B reactivation: Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received bendamustine. Some cases resulted in acute hepatic failure or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with bendamustine. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B tests (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with bendamustine should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
Skin reactions: A number of skin reactions have been reported. These events have included rash, toxic skin reactions and bullous exanthema. Cases of Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), some fatal, have been reported with the use of bendamustine. Patients should be advised of the signs and symptoms of these reactions by their prescribers and should be told to seek medical attention immediately if they develop these symptoms. Some events occurred when bendamustine was given in combination with other anticancer agents, so the precise relationship is uncertain. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, bendamustine should be withheld or discontinued. For severe skin reactions where a relationship to bendamustine is suspected, treatment should be discontinued.
Cardiac disorders: During treatment with bendamustine the concentration of potassium in the blood of patients with cardiac disorders must be closely monitored and potassium supplement must be given when K⁺ <3.5 mEq/l, and ECG measurement must be performed.
Fatal cases of myocardial infarction and cardiac failure have been reported with bendamustine treatment. Patients with concurrent or history of cardiac disease should be observed closely.
Nausea, vomiting: An antiemetic may be given for the symptomatic treatment of nausea and vomiting.
Tumour lysis syndrome: Tumour lysis syndrome associated with bendamustine treatment has been reported in patients in clinical trials. The onset tends to be within 48 hours of the first dose of bendamustine and, without intervention, may lead to acute renal failure and death. Preventive measures include adequate volume status and close monitoring of blood chemistry, particularly potassium and uric acid levels. The use of allopurinol during the first one to two weeks of bendamustine therapy can be considered but not necessarily as standard. However, there have been a few cases of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis reported when bendamustine and allopurinol were administered concomitantly.
Anaphylaxis: Infusion reactions to bendamustine have occurred commonly in clinical trials. Symptoms are generally mild and include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred. Patients must be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids must be considered in subsequent cycles in patients who have previously experienced infusion reactions.
Patients who experienced Grade 3 or worse allergic-type reactions were typically not re-challenged.
Extravasation: An extravasal injection should be stopped immediately. The needle should be removed after a short aspiration. Thereafter the affected area of tissue should be cooled. The arm should be elevated. Additional treatments like the use of corticosteroids are not of clear benefit.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: Histological investigations in dogs showed macroscopic visible hyperaemia of the mucosa and haemorrhagia in the gastrointestinal tract. Microscopic investigations showed extensive changes of the lymphatic tissue indicating an immunosuppression and tubular changes of kidneys and testis, as well as atrophic, necrotic changes of the prostate epithelium.
Animal studies showed that bendamustine is embryotoxic and teratogenic.
Bendamustine induces aberrations of the chromosomes and is mutagenic in vivo as well as in vitro. In long-term studies in female mice bendamustine is carcinogenic.
Effects on ability to drive and use machines: Bendamustine has major influence on the ability to drive and use machines. Ataxia, peripheral neuropathy and somnolence have been reported during treatment with bendamustine. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and using machines.
Use in Pregnancy: Contraception: Bendamustine is teratogenic and mutagenic.
Women should not become pregnant during treatment. Male patients should not father a child during and up to 6 months after treatment. They should seek advice about sperm conservation prior to treatment with bendamustine because of possible irreversible infertility.