Beduras S Injetion

u2022 First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.

u2022 First-line treatment of indolent CD 20 positive non-Hodgkinu2019s lymphoma in combination with rituximab.

u2022 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.

u2022 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

For intravenous infusion over 30 to 60 minutes. Infusion must be administered under the supervision of a medical practitioner qualified and experienced in the use of chemotherapeutic medicines. 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).

Monotherapy for chronic lymphocytic leukaemia

100 mg/m2 body surface area BEDURAS on days 1 and 2; every 4 weeks.

Combination treatment for first-line indolent non-Hodgkinu2019s lymphoma

90 mg/m2 body surface area BEDURAS on days 1 and 2 in combination with 375 mg/m2 body surface area rituximab as a slow IV infusion on day 1; every 4 weeks.

Monotherapy for indolent non-Hodgkinu2019s lymphomas refractory to rituximab

120 mg/m2 body surface area BEDURAS on days 1 and 2; every 3 weeks.

Multiple myeloma

120 u2013 150 mg/m2 body surface area BEDURAS on days 1 and 2, 60 mg/m2 body surface area prednisone IV 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 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.

For preparation and administration instructions see section 6.6.

Special populations

Hepatic impairment

On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment [serum bilirubin 51,3 u03bcmol/L (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

There is no experience in children and adolescents with BEDURAS.

Elderly patients

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

Method of administration

The solution is administered by intravenous (IV) infusion over 30 u2013 60 minutes. The vials are for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

u2022 Hypersensitivity to bendamustine hydrochloride or to any of the excipients in BEDURAS (see section 6.1).

u2022 Pregnancy and lactation (see section 4.6).

u2022 Severe hepatic impairment [serum bilirubin > 34,2 u03bcmol/L (2,0 mg/dL)].

u2022 Jaundice.

u2022 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).

u2022 Major surgery less than 30 days before start of treatment.

u2022 Infections, especially involving leukocytopenia.

u2022 Yellow fever vaccination or any other live (attenuated) vaccination.

u2022 Congenital QT prolongation.

u2022 Concomitant medicines causing QT prolongation.

Myelosuppression

Patients treated with bendamustine hydrochloride, as in BEDURAS, 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/u03bcL or > 100 000/u03bcL, 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/u03bcL) and low CD4- positive T-cell (T- helper cell) counts (< 200/u03bcL) for at least 7 u2013 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/u03bcL) 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 BEDURAS 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, 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 hepatitis B virus (HBV) infection before initiating treatment with BEDURAS. 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 BEDURAS should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).

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), 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 medicines, 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, BEDURAS should be withheld or discontinued. For severe skin reactions with suspected relationship to BEDURAS, 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 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 such as adequate hydration, close monitoring of blood chemistry, particularly potassium and uric acid levels, and the use of hypouricemic medicines (allopurinol and rasbuicase) 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 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 BEDURAS because of possible irreversible infertility (see section 4.6).

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. There are reports of secondary tumours, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukaemia and bronchial carcinoma.

Non-melanoma skin cancer

In clinical studies, an increased risk for non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) has been observed in patients treated with bendamustine containing therapies. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

No in vivo interaction studies have been performed. When BEDURAS is combined with myelosuppressive medicines, the effect of bendamustine hydrochloride and/or the co-administered medicines 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 bendamustine hydrochloride. Combination of bendamustine hydrochloride with cyclosporine or tacrolimus may result in excessive immunosuppression with risk of lymphoproliferation. Cytostatic medicines 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 patients who are already immunosuppressed by their underlying disease. Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme (see section 5.2). Therefore, the potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, aciclovir and cimetidine exists.

Paediatric population

Interaction studies have only been performed in adults.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential must use effective methods of contraception both before and during bendamustine hydrochloride therapy.

Men being treated with bendamustine hydrochloride are advised not to father a child during and for up to 6 months following cessation of treatment.

Pregnancy

There is insufficient data from the use of bendamustine hydrochloride, as in BEDURAS, in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo-/fetolethal, teratogenic and genotoxic. Therefore, BEDURAS is contraindicated during pregnancy (see section 4.3).

Breastfeeding

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

Fertility

Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with bendamustine hydrochloride.

Bendamustine has major influence on the ability to drive a vehicle and use machines. Ataxia, peripheral neuropathy and somnolence have been reported during treatment with bendamustine hydrochloride (see section 4.8). Patients should be instructed that if they experience these symptoms, they should avoid potentially hazardous tasks such as driving and using machines.

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

Adverse reactions in patients treated with bendamustine hydrochloride:

MedDRA system organ class Frequent Less frequent Unknown

Infections and infestations Infection NOS* (including opportunistic infection (e.g. Herpes zoster, cytomegalovirus, hepatitis B)) Pneumocystis jirovecii pneumonia Sepsis Primary atypical pneumonia Tuberculosis

Neoplasms Tumour lysis syndrome Myelodysplastic syndrome Acute myeloid leukaemia

Blood and lymphatic system disorders Leukopenia NOS*, Thrombo-cytopenia Lymphopenia Haemorrhage Anaemia Neutropenia Pancytopenia Bone marrow failure Haemolysis

Immune system disorders Hypersensitivity NOS* 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 dysrhythmia, QT prolongation) Pericardial effusion Myocardial infarction Cardiac failure Tachycardia Atrial fibrillation

Vascular disorders Hypotension Hypertension Acute circulatory failure Phlebitis

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 disorders Hepatic failure

Skin and subcutaneous tissue disorders Alopecia Erythema Stevens-Johnson syndrome Toxic epidermal necrolysis (TEN) Drug reaction with eosinophilia and systemic symptoms (DRESS)

Renal and urinary disorders * Renal failure

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 Decreased: haemoglobin levels Increased: creatinine, urea, AST, ALT, alkaline phosphatase, bilirubin

Hypokalaemia NOS = Not otherwise specified

Description of selected adverse reactions

There have been isolated reports of necrosis after accidental extra-vascular administration and tumour lysis syndrome and anaphylaxis (see section 4.4). The risk of myelodysplastic syndrome and acute myeloid leukaemias is increased in patients treated with alkylating medicines (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 BEDURAS is important. It allows continued monitoring of the benefit/risk balance of BEDURAS. Health care providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org), found on SAHPRAu2019s website.

After application of a 30 minute infusion of bendamustine hydrochloride once every 3 weeks the maximum tolerated dose (MTD) was 280 mg/mu00b2. 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 minute 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.