Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

Myelosuppression
Patients treated with bendamustine hydrochloride 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.
Infections
Serious and fatal infections have occurred with bendamustine hydrochloride, including bacterial (sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), varicella zoster virus (VZV) and cytomegalovirus (CMV). Treatment with bendamustine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride. Some cases resulted in acute hepatic failure or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with bendamustine hydrochloride. 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 hydrochloride should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).
Skin reactions
A number of skin reactions have been reported. These events have included rash, severe cutaneous 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 hydrochloride. 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 hydrochloride was given in combination with other anticancer agents, so the precise relationship is uncertain. When skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, Demustin should be withheld or discontinued. For severe skin reactions with suspected relationship to bendamustine hydrochloride, treatment should be discontinued.


Cardiac disorders
During treatment with bendamustine hydrochloride 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 hydrochloride 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 (TLS) 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 such as adequate hydration, close monitoring of blood chemistry, particularly potassium and uric acid levels and the use of hypouricemic agents (allopurinol and rasburicase) should be considered prior to therapy. 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 hydrochloride 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 cycl e 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.
Contraception
Bendamustine hydrochloride 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 hydrochloride because of possible irreversible infertility.
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.

Effects on Driving

4.7 Effects on ability to drive and use machines

Demustin has major influence on the ability to drive and use machines. Ataxia, peripheral neuropathy and somnolence have been reported during treatment with bendamustine (see section 4.8). Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and using machines.