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. 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 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.

The most common adverse reactions with bendamustine hydrochloride are hematological adverse reactions (leukopenia, thrombopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting).

The table below reflects the data obtained with bendamustine hydrochloride. g. Herpes zoster, cytomegalovirus, hepatitis B) Pneumocystis jirovecii pneumonia Sepsis Pneumonia primary atypical Neoplasms benign, malignant Tumour lysis syndrome Myelodysplastic syndrome, Acute myeloid leukemia Blood and lymphatic system disorders Leukopenia, Thrombocytopenia, Lymphopenia Haemorrhage, Anaemia, Neutropenia Pancytopenia Bone marrow failure Haemolysis Immune system disorders Hypersensitivity Anaphylactic reaction, Anaphylactoid reaction Anaphylactic shock Nervous system disorders Headache Insomnia, Dizziness Somnolence, Aphonia Dysgeusia, Paraesthesia, Peripheral sensory neuropathy, Anticholinergic syndrome, Neurological disorders, Ataxia, Encephalitis Cardiac disorders Cardiac dysfunction, such as palpitations, angina pectoris, Arrhythmia Pericardial effusion, Myocardial infarction, Cardiac failure Tachycardia Atrial fibrillation Vascular Hypotension, Acute Phlebitis MedDRA system organ class 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) disorders Hypertension circulatory failure Respiratory, thoracic and mediastinal disorders Pulmonary dysfunction Pulmonary fibrosis Pneumonitis, Pulmonary alveolar haemorrhage Gastrointestinal disorders Nausea, Vomiting Diarrhoea, Constipation, Stomatitis Haemorrhagic oesophagitis, Gastrointestinal haemorrhage Hepatobiliary disorder Hepatic failure Skin and subcutaneous tissue disorders Alopecia, Skin disorders, Urticaria Erythema, Dermatitis, Pruritus, Maculopapular rash, Hyperhidrosis Stevens – Johnson syndrome, Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Renal and urinary disorders Renal failure Nephrogenic diabetes insipidus Reproductive system and breast disorders Amenorrhea Infertility General disorders and administration site conditions Mucosal inflammation, Fatigue, Pyrexia Pain, Chills, Dehydration, Anorexia Multi organ failure Investigations Haemoglobin decrease, Creatinine increase, Urea increase AST increase, ALT increase, Alkaline phosphatase increase, Bilirubin increase, Hypokalemia * = 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.

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 μ/l) 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.

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.

1 Therapeutic indications 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 progress 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 time of diagnosis precluding the use of thalidomide or bortezomib containing treatment.

2 Posology and method of administration 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. 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.