Bendamustine 25mg & 100mg Fresenius Injection

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

Monotherapy for chronic lymphocytic leukaemia

100 mg/mu00b2 body surface area BENDAMUSTINE FRESENIUS on days 1 and 2; every 4 weeks.

Combination treatment for first-line indolent non-Hodgkinu2019s lymphoma

90 mg/mu00b2 body surface area BENDAMUSTINE FRESENIUS on days 1 and 2 in combination with 375 mg/mu00b2 body surface area rituximab as a slow I.V. infusion on day 1; every 4 weeks.

Monotherapy for indolent non-Hodgkinu2019s lymphomas refractory to rituximab

120 mg/mu00b2 body surface area BENDAMUSTINE FRESENIUS on days 1 and 2; every 3 weeks.

Multiple Myeloma

120-150 mg/mu00b2 body surface area BENDAMUSTINE FRESENIUS on days 1 and 2, 60 mg/mu00b2 body surface area prednisone I.V. or orally on days 1 to 4; every 4 weeks.

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 patients

There is no experience in children and adolescents with BENDAMUSTINE FRESENIUS.

Elderly patients

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

Method of Administration

Precaution to be taken before manipulating or administering the product. When handling BENDAMUSTINE FRESENIUS , 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 (see section 6.6).

For intravenous infusion over 30 to 60 minutes. Infusion must be administered under the supervision of a medical physician 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 have dropped to < 3 x 10 9 /L or 4 x 10 9 /L and platelet values to > 100 x 10 9 /L. 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 (see section 4.4). In the 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. For instructions on reconstitution and dilution of the medicine , see section 6.6.

u2022 Hypersensitivity to the active substance or to any of the excipients listed in 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 10 9 /L or < 75 x 10 9 /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 FRESENIUS may 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 10/u03bcL or > 100 x 10/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). Treatment with bendamustine hydrochloride may cause prolonged lymphocytopenia (< 600/u03bc L) and low CD4-positive T-cell (T- helper cell) counts (< 200/u03bc L) for at least 7u20139 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/u03bc L) 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).

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 FRESENIUS should be considered if there are signs of (opportunistic) infections. The presence of tuberculosis should be excluded before treatment with BENDAMUSTINE FRESENIUS is commenced.

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 FRESENIUS 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 u2013 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 medicines, so the precise relationship is uncertain. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, BENDAMUSTINE FRESENIUS should be withheld or discontinued. For severe skin reactions where a relationship to bendamustine hydrochloride is suspected, treatment should be discontinued.

Cardiac disorders

During treatment with BENDAMUSTINE FRESENIUS 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 and close monitoring of blood chemistry, particularly potassium and uric acid levels, and the use of hypouricemic medicines (allopurinol) 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. Due to the potential for genotoxicity, advise female patients of reproductive potential to use highly effective contraception during treatment and for 6 months after the last dose of BENDAMUSTINE FRESENIUS. Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of BENDAMUSTINE FRESENIUS. They should seek advice about sperm conservation prior to treatment with BENDAMUSTINE FRESENIUS 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.

Other malignancies

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

No in-vivo interaction studies have been performed. When BENDAMUSTINE FRESENIUS is combined with myelosuppressive medicines, the effect of bendamustine and/or the co-administered medicines on the bone marrow may be potentiated. Any treatment reducing the patientu2019s performance status or impairing bone marrow function can increase the toxicity of bendamustine. Combination of BENDAMUSTINE FRESENIUS 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 (see section 5.2). Therefore, potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir, and cimetidine exist. Incompatibilities: This medicine must not be mixed with other medicines except those mentioned in section 6.6.

Women of childbearing potential/contraception/ fertility

Women of childbearing potential must use highly effective contraception during treatment and for 6 months after the last dose of BENDAMUSTINE FRESENIUS. Men being treated with BENDAMUSTINE FRESENIUS are advised not to father a child during and for up to 3 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 BENDAMUSTINE FRESENIUS.

Pregnancy

There are no adequate data from the use of bendamustine hydrochloride in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo-/foetolethal, teratogenic and genotoxic. (see section 5.3). Therefore, BENDAMUSTINE FRESENIUS is contraindicated during pregnancy (see section 4.3).

Breastfeeding

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

BENDAMUSTINE FRESENIUS has major influence on the ability to drive 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 common side effects with BENDAMUSTINE FRESENIUS are haematological adverse reactions (leukopenia, thrombocytopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting). The table below reflects the data obtained with bendamustine hydrochloride.

Table 1: Adverse reactions in patients treated with bendamustine hydrochloride.

MedDRA system organ class Frequent Less Frequent Frequency unknown Infections and infestations Infection NOS* Including Opportunistic infection (including Herpes zoster, cytomegalovirus, hepatitis B) Pneumocystis jirovecii pneumonia Sepsis tuberculosis Pneumonia primary atypical Neoplasms benign, malignant and unspecified (including cyst and polyp) Tumour lysis syndrome Myelodysplasti c syndrome, acute myeloid leukaemia Blood and lymphatic system disorders Leukopenia NOS*, Thrombocytopenia, Lymphopenia Haemorrhage, Anaemia, Neutropenia Bone marrow failure Pancytopenia Haemolysis Immune system disorders Hypersensitivity NOS* Anaphylactic reaction, Anaphylactoid reaction Anaphylactic shock Metabolism and nutrition disorders Tumour lysis syndrome

MedDRA system organ class Frequent Less Frequent Frequency unknown 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 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

MedDRA system organ class Frequent Less Frequent Frequency unknown Gastrointestin al disorders Nausea, Vomiting Diarrhoea, Constipation, Stomatitis Haemorrhagic oesophagitis, Gastrointestin al haemorrhage Skin and subcutaneous tissue disorders Alopecia, Skin disorders NOS*, Urticaria Erythema, Dermatitis, Pruritus, Maculopapular, Rash, Hyperhidrosis Bullous Exanthema Stevens u2013 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 Amenorrhea Infertility

MedDRA system organ class Frequent Less Frequent Frequency unknown breast disorders Hepatobiliary disorders Hepatic failure General disorders and administration site conditions Mucosal inflammation, Fatigue, Pyrexia Pain, Chills, Dehydration, Anorexia Multi organ failure Investigations Decrease haemoglobin, Increase creatinine, Increase urea Increase AST, Increase ALT, Increase alkaline phosphatase, Increase bilirubin, Hypokalemia

*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. The risk of myelodysplastic syndrome and acute myeloid leukaemias is increased in patients treated with alkylating medicine s (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 benefit/risk balance of the medicine. Healthcare providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Healthcare providers are asked to report any suspected adverse drug reactions to the Holder of the Certificate of Registration at the following email address: [email protected] and to the relevant medicineu2019s regulatory authority in the country where the product is marketed.

After application of a 30 min 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 min infusion of bendamustine hydrochloride at day 1 and 2 every 3 weeks the MTD was found to be 180 mg/mu00b2. 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.