Bendahet Injection

BENDAHET is indicated for the following conditions:

• First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
• First-line treatment of indolent CD 20 positive non-Hodgkinu2019s lymphoma in combination with rituximab
• Indolent non-Hodgkinu2019s 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.

Posology

Monotherapy for chronic lymphocytic leukaemia 100 mg/m2 body surface area BENDAHET on days 1 and 2; every 4 weeks.

Combination treatment for first-line indolent non-Hodgkinu2019s lymphoma 90 mg/m2 surface area BENDAHET on days 1 and 2 in combination with 375 mg/m2 body surface area rituximab as a slow i.v. infusion on day 1; every 4 weeks.

Monotherapy for indolent non-Hodgkin's lymphomas refractory to rituximab 120 mg/m2 body surface area BENDAHET on days 1 and 2; every 3 weeks.

Multiple Myeloma 120 u2013 150 mg/m2 body surface area BENDAHET on days 1 and 2, 60 mg/m2 body surface area prednisone intravenous or orally on days 1 to 4; every 4 weeks.

Treatment should be terminated or delayed if leukocyte and/or platelet values dropped to u2264 3 x 109/L or u2264 75 x 109/L, respectively. Treatment can be continued after leukocyte values have increased to > 4 x 109/L and platelet values to > 100 x 109/L. The leukocyte and platelet Nadir is reached, after 14 u2013 20 days with regeneration after 3 u2013 5 weeks. During therapy free intervals strict monitoring of the blood count is recommended (see section 4.4).

In case of non-haematological toxicity dose reductions have to be based on the worst CTC (common toxicity scale) 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.

Special populations

Elderly patients There is no evidence that dose adjustments are necessary in elderly patients (see section 5.2).

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.

Hepatic impairment On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment [serum bilirubin 3,0 mg/dL (51,3 u03bcmol/L)].

Paediatric population There is no experience in children and adolescents with BENDAHET

Method of administration

Precautions to be taken before manipulating or handing medicine When handling BENDAHET, inhalation, skin contact or contact with mucous membranes should be avoided (wear gloves and protective clothes). Contaminated body parts should be carefully rinsed with water and soap; the eye should be rinsed with physiological saline solution. If possible, it is recommended to work on special safety workbenches (laminar flow) with liquid impermeable, absorbing disposable foil. Pregnant personnel should be excluded from handling cytostatics.

For instructions on reconstitution of the medicine (see section 6.6).

BENDAHET is administered by intravenous infusion over 30 u2013 60 min. 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 x 109/L or < 75 x 109/L, respectively (see section 4.3).

• Hypersensitivity to bendamustine or any of the excipients in BENDAHET.
• Pregnancy and lactation.
• Severe hepatic impairment [serum bilirubin > 2,0 mg/dL (34,2 u03bcmol/L)].
• Jaundice
• Severe bone marrow suppression and severe blood count alterations (leukocyte and/or platelet values dropped to < 3 x 109/L or < 75 x 109/L, respectively).
• Major surgery less than 30 days before the start of treatment.
• Infections, especially involving leukocytopenia.
• Yellow fever vaccination or any other live (attenuated) vaccination
• Congenital QT prolongation
• Concomitant medicines causing QT prolongation.

Myelosuppression Patients treated with bendamustine hydrochloride experience myelosuppression. 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 x 109/L or > 100 x 109/L, respectively.

Infections Serious infection, including pneumonia and sepsis, has been reported with bendamustine hydrochloride. Infection has been associated with hospitalisation, septic shock and death. Patients with neutropenia and/or lymphopenia following treatment with bendamustine hydrochloride are more susceptible to opportunistic infections. Opportunistic infection such as Pneumocystis jirovecii pneumonia (PJP), varicella zoster virus (VZV) and cytomegalovirus (CMV) have been reported. Treatment with bendamustine hydrochloride may cause prolonged lymphocytopenia (< 600/u03bcl) and low CD4-positive T-cell (T-helper cell) counts (< 200/u03bcl) for at least 7 u20139 months after the completion of treatment. Lymphocytopenia and CD4-positive T-cell depletion is more pronounced when bendamustine is combined with rituximab. In case of low CD4-positive T-cell counts (< 200/u03bcl) Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be considered. Cases of tuberculosis have been less frequently reported compared to other infections. Latent or dormant tuberculosis may become active. (see section 4.8) Patients with myelosuppression following BENDAHET treatment should be advised to contact a medical practitioner if they have symptoms or signs of infection, including fever or respiratory symptoms. Discontinuation of bendamustine hydrochloride should be considered if there are signs of opportunistic infections. The presence of tuberculosis should be excluded before treatment with BENDAHET is commenced.

Skin reactions A number of skin reactions have been reported. These events have included rash, severe cutaneous reactions and bullous exanthema. Cases of Stevens u2013 Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), some fatal, have been reported with the use of bendamustine hydrochloride. (see section 4.8). 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 of these events occurred when bendamustine hydrochloride was given in combination with other anticancer agents. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, BENDAHET should be withheld or discontinued. For severe skin reactions where a relationship to BENDAHET is suspected, treatment should be discontinued.

Cardiac disorders During treatment with BENDAHET the concentration of potassium in the blood of cardiac patients must be closely monitored. When serum potassium levels are < 3,5 mEq/L, an ECG measurement must be performed, and potassium supplement must be given. 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 should be given for the symptomatic treatment of nausea and vomiting.

Tumour lysis syndrome Tumour lysis syndrome 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 bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include adequate volume status and close monitoring of blood chemistry, particularly potassium and uric acid levels. The use of allopurinol during the first one to two weeks of BENDAHET therapy can be considered. However, there have been a few cases of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis reported when bendamustine hydrochloride 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. 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. In patients who experienced Grade 3 or worse allergic-type reactions, BENDAHET should be discontinued.

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 BENDAHET 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. There have been reports of necrosis after accidental extra-vascular administration and toxic epidermal necrosis, tumour lysis syndrome, and anaphylaxis (see section 4.8).

Other malignancies There have been reports of secondary tumours, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukaemia and bronchial carcinoma.

No in vivo interaction studies have been performed. When BENDAHET is combined with myelosuppressive agents, the effect of BENDAHET 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 BENDAHET. Combination of BENDAHET with ciclosporin 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 hydrochloride metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir, and cimetidine exist. CYP1A2 inducers, such as omeprazole, can reduce exposure to bendamustine.

Women of child-bearing potential Women of childbearing potential must use effective methods of contraception both before and during BENDAHET therapy.

Pregnancy There is no adequate data from the use of BENDAHET in pregnant women. In non-clinical studies bendamustine hydrochloride was embryo-/foetolethal, teratogenic and genotoxic. Therefore, BENDAHET is contraindicated during pregnancy (see section 4.3).

Breastfeeding It is not known whether bendamustine hydrochloride passes into the breast milk, therefore it BENDAHET is contraindicated during breastfeeding (see section 4.3). Breastfeeding must be discontinued during treatment with BENDAHET.

Fertility Men being treated with BENDAHET are advised not to father a child during and for up to 6 months following cessation of treatment. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with BENDAHET.

Bendamustine hydrochloride may cause side effects such as ataxia, peripheral neuropathy and somnolence (see section 4.8). This may influence the ability to drive and use machines. Patients should be advised not to drive or operate machines if they experience these effects.

a. 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).

b. Tabulated list of adverse reactions Infections and Infestations Frequent: Infection (not otherwise specified), opportunistic infections (including Herpes zoster, cytomegalovirus, hepatitis B) Less frequent: Septicaemia, primary atypical pneumonia, Pneumocystis jiroveci pneumonia, tuberculosis (TB) Neoplasm benign and malignant Frequent Tumour lysis syndrome Less frequent Myelodysplastic syndrome, acute myeloid leukaemia Blood and the lymphatic system disorders Frequent: Leukopenia (not otherwise specified), thrombocytopenia, haemorrhage, anaemia, neutropenia, lymphopenia, myelosuppression Less frequent: Haemolysis, Pancytopenia, bone marrow failure. Immune system disorders Frequent: Hypersensitivity (not otherwise specified) Less frequent: Anaphylactic reaction, anaphylactoid reaction, anaphylactic shock Nervous system disorders Frequent: Insomnia, headache, dizziness Less frequent: Somnolence, aphonia, dysgeusia, paraesthesia, peripheral sensory neuropathy, anticholinergic syndrome, neurological disorders, ataxia, encephalitis Cardiac disorders Frequent: Cardiac dysfunction, such as palpitations, angina pectoris, dysrhythmia Less frequent: Pericardial effusion, tachycardia, myocardial infarction, cardiac failure Frequency unknown Atrial fibrillation Vascular disorders Frequent: Hypotension, hypertension Less frequent: Acute circulatory failure, phlebitis Respiratory, thoracic and mediastinal disorders Frequent: Pulmonary dysfunction Less frequent: Pulmonary fibrosis Frequency unknown Pneumonitis, pulmonary alveolar haemorrhage Hepato-biliary disorders Frequency unknown Hepatic failure Gastrointestinal disorders Frequent: Nausea, vomiting, diarrhoea, constipation, stomatitis, dry mouth Less frequent: Haemorrhagic oesophagitis, gastrointestinal haemorrhage Skin and subcutaneous tissue disorders Frequent: Alopecia, skin disorders (not otherwise specified) Less frequent: Erythema, dermatitis, pruritus, maculopapular rash, hyperhidrosis Frequency unknown: Bullous exanthema, Stevens u2013 Johnson syndrome, Toxic Epidermal Necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)* Renal and urinary disorders Frequency unknown Renal failure Reproductive system and breast disorders Frequent: Amenorrhoea Less frequent: Infertility General disorders and administration site conditions Frequent: Mucosal inflammation, fatigue, pyrexia, pain, chills, dehydration, anorexia Less frequent: Multiple organ failure Investigations Frequent: Decrease haemoglobin, increase creatinine, increase urea, Increase AST, increase ALT, increase alkaline phosphatase, increase bilirubin, hypokalaemia.

c. 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 leukemias 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 medicine is important. It allows continued monitoring of the risk/benefit ratio of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via u20186.04 Adverse Drug Reactions Formu2019 available online under SAHPRAu2019s publications at https://www.sahpra.org.za/publications/Index/8/ or to the Holder of Certificate of Registration through the mail, [email protected]. By reporting adverse reactions you can help provide more information on the safety of BENDAHET.

After application of a 30 min infusion of bendamustine hydrochloride once every 3 weeks the maximum tolerated dose (MTD) was 280 mg/m2. Cardiac events of CTC (common toxicity scale) 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 hydrochloride 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 dialysable to a small extent.