BENDAMUSTINE HYDROCHLORIDE

Posology Monotherapy for chronic lymphocytic leukaemia 100 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2; every 4 weeks up to 6 times. Monotherapy for indolent non-Hodgkin's lymphomas refractory to rituximab 120 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2; every 3 weeks for at least 6 times.

v. or per os on days 1 to 4; every 4 weeks for at least 3 times. 2 mg/dl). 0 mg/dl). 3). Renal impairment On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with a creatinine clearance of >10 ml/min. Experience in patients with severe renal impairment is limited.

Paediatric population The safety and efficacy of bendamustine hydrochloride in children have not yet been established. Current available data is not sufficient to make a recommendation on posology. 2). 6). Infusion must be administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents.

Poor bone marrow function is related to increased chemotherapy-induced haematological toxicity. 3). Treatment should be terminated or delayed if leukocyte and/or platelet values have dropped to <3,000/μl or <75,000/μl, respectively. Treatment can be continued after leukocyte values have increased to >4,000/μl and platelet values to >100,000/μl.

The leukocyte and platelet nadir is reached after 14-20 days with regeneration after 3- 5 weeks. 4). In case of non-haematological toxicity dose reductions have to be based on the worst Common Toxicity Criteria (CTC) grades in the preceding cycle.

A 50% dose reduction is recommended in case of CTC Grade 3 toxicity. An interruption of treatment is recommended in case of CTC Grade 4 toxicity. If a patient requires a dose modification the individually calculated reduced dose must be given on day 1 and 2 of the respective treatment cycle.

6.

Summary of the safety profile The most common adverse reactions with bendamustine hydrochloride are haematological adverse reactions (leukopenia, thrombopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting).

Tabulated list of adverse reactions The table below reflects the data obtained with bendamustine hydrochloride in clinical trials. Adverse reactions listed below are classified according to frequency and system organ class (SOC). The frequencies of adverse reactions are ranked according to the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1:

Adverse reactions in patients treated with bendamustine hydrochloride. g. Herpes zoster, cytomegal ovirus, hepatitis B) Pneumocy stis, jirovecii pneumonia Sepsis Pneumonia primary atypical Neoplasms benign, malignant and Tumour lysis syndrome Myelodysp last ic syndrome, acute unspecifie d (incl cysts and polyps) myeloid leukemia Blood and lymphatic system disorders Leukocyto -penia NOS, thrombocy to-penia, lymphopen ia Haemorrha ge, anaemia, neutropeni a Pancytope nia Bone marram failure Haemolysi s Immune system disorders Hypersen- sitivity NOS Anaphylac -tic reaction, anaphylac- toid reaction Anaphylac tic shock Nervous system disorders Headache Insomnia, dizziness Somnolenc e, aphonia Dysgeusia, paraesthesi a, peripheral sensory neuropathy , antichol- inergic syndrome, neurologic al disorders, ataxia, encephaliti s Cardiac disorders Cardiac dysfunctio n, such as palpitation s, angina pectoris, arrhythmia Pericardial effusion, myocardial infarction, cardiac failure Tachycardi a, Atrial fibrillation Vascular disorders Hypotensi on, hypertensi on Acute circulatory failure Phlebitis Respirator y, thoracic and mediastina l disorders Pulmonary dysfunctio n Pulmonary fibrosis Pneumoni tis, pulmonar alveolar haemorrha Gastrointes tinal Nausea, vomiting Diarrhoea, constipatio Haemorr- hagic disorders n, stomatitis oesophagit is, gastrointes tinal haemorrha ge Hepatobili ary disorders Hepatic failure Skin and subcutaneo us tissue disorders Alopecia, skin disorders NOS, urticaria Erythema, dermatitis, pruritus, macular- papular rash, hyper- hydrosis Stevens – Johnson syndrome, Toxic Epidermal Necrolysis (TEN), drug reaction with eosinophil ia and systemic symptoms (DRESS)* Renal and urinary disorders Renal failure Reproducti ve system and breast disorders Amenorrh oea Infertility General disorders and administrat ion site conditions Mucosal inflammati on, fatigue, pyrexia Pain, chills, dehydratio n, anorexia Multi organ failure Investigati ons Haemoglo bin decrease, creatinine increase, urea increase AST increase, ALT increase, alkaline phosphatas e increase, bilirubin increase, hypokalae mia NOS = Not otherwise specified (*=combination therapy with rituximab) Description of selected adverse reactions There have been isolated reports of necrosis after accidental extra-vascular administration and tumour lysis syndrome and anaphylaxis.

The risk of myelodysplastic syndrome and acute myeloid leukaemias is increased in patients treated with alkylating agents (including bendamustine). The secondary malignancy may develop several years after chemotherapy has been discontinued.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard.

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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).

Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of bendamustine mainly in combination with rituximab or obinutuzumab. 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.

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.

Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected then appropriate diagnostic evaluations should be undertaken and treatment suspended until PML is excluded.

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.

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, {Invented name} should be withheld or discontinued. For severe skin reactions with suspected relationship to bendamustine hydrochloride, treatment should be discontinued.

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 hydrochloride treatment has been reported in patients in clinical trials.

The onset tends to be within 48 hours of the first dose of {Invented name} 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 are 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 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.

Contraception Bendamustine hydrochloride is teratogenic and mutagenic. Women should not become pregnant during treatment. Male patients should not father a child […]

1. 0 mg/dl) - Jaundice - Severe bone marrow suppression and severe blood count alterations (leukocyte and/or platelet values dropped to <3,000/μl or <75,000/μl, respectively) - Major surgery less than 30 days before start of treatment - Infections, especially involving leukocytopenia - Yellow fever vaccination