BENDAMUSTINE ACCORD 25MG/ML Concentrate for solution for infusion

Myelosuppression Myelosuppression may occur in patients treated with bendamustine hydrochloride. In the case of treatment-induced myelosuppression, leukocyte counts, platelet counts, haemoglobin levels and neutrophil counts must be monitored at least weekly. The next treatment cycle is recommended only after the following parameters have been achieved: leukocyte and/or platelet values > 4,000/µl and > 100,000/µl, respectively. Infections Serious and fatal infections have occurred with bendamustine hydrochloride, including bacterial infections (sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), varicella zoster virus (VZV) and cytomegalovirus (CMV). Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported following use of bendamustine, particularly in combination with rituximab or obinutuzumab. Treatment with bendamustine hydrochloride may cause prolonged lymphocytopenia (< 600/μl) and low CD4-positive T-cell counts (helper T-cells) (< 200/μl), which may persist for at least 7–9 months after the end of treatment. Lymphocytopenia and depletion of CD4-positive T-cells are more pronounced when bendamustine is combined with rituximab. Patients with lymphopenia and low CD4-positive T-cell counts are more susceptible to (opportunistic) infections after treatment with bendamustine hydrochloride. In the case of low CD4-positive T-cell counts (< 200/μl), prophylaxis against Pneumocystis jirovecii pneumonia (PJP) should be considered. All patients should be monitored during treatment for respiratory difficulties and symptoms. Patients should be advised to report any new signs of infection promptly, including fever or respiratory symptoms. In the case of signs of (opportunistic) infections, discontinuation of bendamustine hydrochloride should be considered. In patients with new or worsening neurological, cognitive or behavioural signs or symptoms, PML should be considered in the differential diagnosis. If PML is suspected, appropriate diagnostic evaluations should be performed and treatment should be delayed until PML has been excluded. Hepatitis B reactivation Reactivation of hepatitis B has occurred in patients who are chronic carriers of the hepatitis B virus after administration of bendamustine hydrochloride. Some cases resulted in acute hepatic failure or death. Patients should be tested for HBV infection before starting treatment with bendamustine hydrochloride. Patients with positive hepatitis B serology (including those with active disease) should consult with hepatologists and specialists in the treatment of hepatitis B before commencing treatment; the same applies for patients who test positive for HBV infection during treatment. HBV carriers who require treatment with bendamustine hydrochloride should be carefully monitored during treatment and for several months after completion of treatment for signs and symptoms of active HBV infection (see section 4.8 ). Skin reactions Numerous skin reactions have been reported, including rash, severe skin reactions and bullous exanthema. Cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with bendamustine hydrochloride, some of them fatal. Patients should be advised by the prescribing physician about the signs and symptoms of these reactions and should be instructed to seek immediate medical attention if these symptoms occur. Some of these cases occurred when bendamustine hydrochloride was administered in combination with other antineoplastic agents; therefore, the exact relationship is uncertain. If skin reactions occur, they may progress with continued treatment and their severity may increase. If skin reactions progress, bendamustine administration should be interrupted or discontinued. In the case of severe skin reactions with suspected relationship to bendamustine hydrochloride, treatment should be discontinued. Cardiac disorders During treatment with bendamustine hydrochloride, serum potassium levels must be carefully monitored in patients with cardiac disorders, and potassium supplements must be administered when K + < 3.5 mEq/l; ECG monitoring must also be performed. Fatal cases of myocardial infarction and cardiac failure have been reported during treatment with bendamustine hydrochloride. Patients with cardiac disease, including a history of cardiac disease, should be carefully monitored. Nausea, vomiting Antiemetics may be administered 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 studies. It typically manifests within 48 hours after the first dose of bendamustine and, if untreated, may lead to acute renal failure and death. Prior to initiation of treatment, preventive measures should be considered, such as ensuring adequate hydration, close monitoring of blood chemistry parameters, particularly potassium and uric acid levels, and the use of hypouricaemic agents (allopurinol and rasburicase). Several cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with concomitant administration of bendamustine and allopurinol. Anaphylaxis Infusion reactions to bendamustine hydrochloride occurred commonly in clinical studies. Symptoms are usually mild and include fever, chills, pruritus and rash. In rare cases, severe anaphylactic and anaphylactoid reactions have occurred. After the first cycle of treatment, patients should be asked whether they experienced symptoms suggestive of an infusion reaction. In patients who have previously experienced infusion reactions, preventive measures against severe reactions should be considered during subsequent cycles, including antihistamines, antipyretics and corticosteroids. Patients who experienced allergic-type reactions of grade 3 or higher were generally not re-treated. Contraception Bendamustine hydrochloride is teratogenic and mutagenic. Women must not become pregnant during treatment. Men should be advised about sperm preservation prior to starting treatment with bendamustine hydrochloride due to the possibility of irreversible infertility. Extravasation Extravasation injection must be stopped immediately. After brief aspiration, the needle must be removed. The affected tissue area should then be cooled. The arm should be elevated. Additional treatment, such as administration of corticosteroids, has no clear benefit. Non-melanoma skin cancer An increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) has been observed in clinical studies in patients receiving bendamustine-containing treatment. Regular skin examinations are recommended for all patients, particularly those with risk factors for skin cancer. Dilution Bendamustine Accord requires appropriate dilution before use. The concentration of bendamustine in Bendamustine Accord 25 mg/ml concentrate for solution for infusion differs from other bendamustine-containing products (for further dilution instructions, see section 6.6).