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  • Demustin
    / Rafa


    Active Ingredient

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Vial

    5 X 25 mg

    not in the basket chart 63470

    Vial

    5 X 100 mg

    not in the basket chart 63471

    Related information


    Dosage

    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.
    Follicular non-Hodgkin’s lymphoma: Combination with rituximab: The dose is 90 mg/m² body surface area Demustin I.V. on days 1 and 2 plus 375 mg/m² rituximab on day 1; repetition every 4 weeks.
    Hepatic impairment: On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment (serum bilirubin < 1.2mg/dl). A 30% dose reduction is recommended in patients with moderate hepatic impairment (serum bilirubin 1.2 – 3.0 mg/dl).
    No data is available in patients with severe hepatic impairment (serum bilirubin values of > 3.0 mg/dl).
    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.
    Elderly patients: There is no evidence that dose adjustments are necessary in elderly patients.
    Method of administration: For intravenous infusion over 30 – 60 minutes.
    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. Treatment should not be started if leukocyte and/or platelet values dropped to < 3,000/µl or < 75,000/µl, respectively.
    Treatment should be terminated or delayed if leukocyte and/or platelet values 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. During therapy free intervals strict monitoring of the blood count is recommended.
    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.


    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.
    Follicular non-Hodgkin’s lymphoma as first line treatment in combination with rituximab.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients.
    During breastfeeding.
    Severe hepatic impairment (serum bilirubin > 3.0 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.


    Special Precautions

    Myelosuppression: Patients treated with bendamustine hydrochloride may experience myelosuppression. In the event of treatmentrelated 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.
    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 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 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.


    Side Effects

    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).
    See prescribing information for full details.


    Drug interactions

    No in-vivo interaction studies have been performed.
    When Demustin is combined with myelosuppressive agents, the effect of Demustin and/or the co-administered medicinal products on the bone marrow may be potentiated. Any treatment reducing the patient’s performance status or impairing bone marrow function can increase the toxicity of Demustin.
    Combination of Demustin with cyclosporine or tacrolimus may result in excessive immunosuppression with risk of lymphoproliferation.
    Cytostatics can reduce antibody formation following live-virus vaccination and increase the risk of infection which may lead to fatal outcome. This risk is increased in subjects who are already immunosuppressed by their underlying disease.
    Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, the potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir and cimetidine exists.
    Paediatric population: Interaction studies have only been performed in adults.


    Pregnancy and Lactation

    Pregnancy: There are insufficient data from the use of Demustin in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo-/fetolethal, teratogenic and genotoxic. During pregnancy Demustin
    should not be used unless clearly necessary. The mother should be informed about the risk to the foetus. If treatment with Demustin is absolutely necessary during pregnancy or if pregnancy occurs during treatment, the patient should be informed about the risks for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered.
    Lactation: It is not known whether bendamustine passes into the breast milk, therefore, Demustin is contraindicated during breast feeding. Breast feeding must be discontinued during treatment with Demustin.


    Overdose

    After application of a 30 min infusion of bendamustine once every 3 weeks the maximum tolerated dose (MTD) was 280 mg/m². Cardiac events of CTC grade 2 which were compatible with ischaemic ECG changes occurred which were regarded as dose limiting.
    In a subsequent study with a 30 min infusion of bendamustine at day 1 and 2 every 3 weeks the MTD was found to be 180 mg/m². The dose limiting toxicity was grade 4 thrombocytopenia. Cardiac toxicity was not dose limiting with this schedule.
    Counter measures: There is no specific antidote. Bone marrow transplantation and transfusions (platelets, concentrated erythrocytes) may be made or haematological growth factors may be given as effective countermeasures to control haematological side effects.
    Bendamustine hydrochloride and its metabolites are dialyzable to a small extent.


    Manufacturer
    Intas Pharmaceuticals
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