Baximo 25 mg/100 mg Powder

• 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-Hodgkin's lymphoma 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/mu00b2 body surface area BAXIMO on days 1 and 2; every 4 weeks.
• Combination treatment for first-line indolent non-Hodgkinu2019s lymphoma: 90 mg/mu00b2 body surface area BAXIMO on days 1 and 2 in combination with 375 mg/mu00b2 body surface area rituximab as a slow intravenous infusion on day 1 every 4 weeks.
• Monotherapy for indolent non-Hodgkinu2019s lymphoma refractory to rituximab: 120 mg/mu00b2 body surface area BAXIMO on days 1 and 2 every 3 weeks.
• Multiple myeloma: 120 u2013 150 mg/mu00b2 body surface area BAXIMO on days 1 and 2, 60 mg/mu00b2 body surface area prednisone intravenous 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 (3,0mg/dL)]. See section 4.3.

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 patients: There is no experience in children and adolescents with BAXIMO.

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

Method of administration: For intravenous infusion over 30 u2013 60 minutes. Infusion must be administered under the supervision of a medical practitioner qualified and experienced in the use of chemotherapeutic medicines.

• Hypersensitivity to bendamustine hydrochloride or to any of the excipients in BAXIMO (see section 6.1).
• Pregnancy and lactation (see section 4.6).
• Severe hepatic impairment [serum bilirubin > 34,2 u03bcmol/L (2,0 mg/dL)].
• Jaundice.
• Severe bone marrow suppression and severe blood count alterations (leukocyte and/or platelet values dropped to < 3 x 10 9 /L or < 75 x10 9 /L, respectively).
• Major surgery less than 30 days before start of treatment.
• Infections, especially involving leukocytopenia.
• Yellow fever vaccination or any other live (attenuated) vaccination.
• Congenital QT prolongation.
• Concomitant medicines causing QT prolongation (see section 4.5).

Myelosuppression: Patients treated with bendamustine hydrochloride as in BAXIMO 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 x 10 9 /L or > 100 x 10 9 /L, 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). BAXIMO 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 BAXIMO is combined with rituximab. Patients with lymphopenia and low CD4-positive T-cell count following treatment with BAXIMO are more susceptible to (opportunistic) infections, including tuberculosis. 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 BAXIMO should be considered if there are signs of (opportunistic) infections. Infection, including pneumonia and sepsis, has been reported. Infection has been associated with hospitalisation, septic shock and death. Patients with neutropenia and/or lymphopenia following treatment with BAXIMO are more susceptible to infections, including tuberculosis. Patients with myelosuppression following BAXIMO treatment should be advised to contact a medical practitioner if they have symptoms or signs of infection, including fever or respiratory symptoms. The presence of tuberculosis should be excluded before treatment with BAXIMO is commenced.

Hepatitis B reactivation: Reactivation of hepatitis B in patients who are chronic carriers of this virus may occur after patients received bendamustine hydrochloride, as in BAXIMO. Some cases resulted in acute hepatic failure or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with BAXIMO. 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 BAXIMO 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) and toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), some fatal, have been reported with the use of BAXIMO. Patients should be advised of the signs and symptoms of these reactions by their medical practitioner and should be told to seek medical attention immediately if they develop these symptoms. Some events occurred when BAXIMO 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, BAXIMO should be withheld or discontinued. For severe skin reactions with suspected relationship to BAXIMO, treatment should be discontinued.

Cardiac disorders: During treatment with BAXIMO 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 and vomiting: An antiemetic may be given for the symptomatic treatment of nausea and vomiting.

Tumour lysis syndrome: Tumour lysis syndrome (TLS) associated with BAXIMO treatment has been reported. The onset tends to be within 48 hours of the first dose of BAXIMO and, without intervention, may lead to acute renal failure and death. Preventative measures include adequate fluid volume status and close monitoring of blood chemistry, particularly potassium and uric acid levels. The use of hypouricaemic medicines (allopurinol and rasburicase) during the first one to two weeks of BAXIMO therapy can be considered. However, there have been cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported when bendamustine, as in BAXIMO, and allopurinol were administered concomitantly.

Anaphylaxis: Infusion reactions to bendamustine hydrochloride, as in BAXIMO, have occurred. Symptoms 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, BAXIMO should be discontinued.

Contraception: Bendamustine hydrochloride, as in BAXIMO, is teratogenic and mutagenic. Women should not become pregnant during treatment. Women of childbearing potential must use effective contraception to avoid pregnancy while they are receiving BAXIMO. The recommended duration of contraception in female patients of childbearing potential is until the end of the relevant systemic exposure to BAXIMO including potential metabolites (i.e.: five half-lifeu2019s after the last dose) plus 6 months. On this basis, female patients of childbearing potential should be advised to use effective contraception during treatment with BAXIMO and for at least 6 months after the final dose. Male patients should not father a child during treatment and should be advised on the use of effective contraception to avoid conception. The recommended duration of contraception in male patients is until the end of the relevant systemic exposure to BAXIMO including potential metabolites (i.e.: five half-lifeu2019s after the last dose) plus 3 months. On this basis male patients should be advised on the use of effective contraception during treatment with BAXIMO and for at least 3 months after the final dose (see section 4.6). They should seek advice about sperm conservation prior to treatment with bendamustine hydrochloride, as in BAXIMO, 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 extravascular administration and toxic epidermal necrosis, tumour lysis syndrome and anaphylaxis. 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 BAXIMO is combined with myelosuppressive medicines, the effect of BAXIMO 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 BAXIMO. Combination of BAXIMO 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. BAXIMO 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.

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

Women of childbearing potential: Women of childbearing potential must use effective methods of contraception to avoid pregnancy while they are receiving BAXIMO, and for at least 6 months following completion of treatment (i.e.: after the final dose).

Male Fertility: BAXIMO can have genotoxic effects. Men being treated with BAXIMO are advised not to father a child during and for up to 3 months following cessation of treatment (i.e.: after the final dose). Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with BAXIMO.

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

BAXIMO has a major influence on the ability to drive a vehicle and use machines. Ataxia, peripheral neuropathy and somnolence have been reported during treatment with BAXIMO (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.

MedDRA System Organ Class Frequency and description

• Infections and infestations: Frequent: infection (not otherwise specified), including opportunistic infection (e.g. Herpes zoster, cytomegalovirus, hepatitis B). Less frequent: Pneumocystis jirovecii pneumonia, sepsis, primary atypical pneumonia, tuberculosis.
• Neoplasms benign, malignant and unspecified (including cysts and polyps): Frequent: tumour lysis syndrome. Less frequent: myelodysplastic syndrome, acute myeloid leukaemia.
• Blood and lymphatic system disorders: Frequent: leukopenia (not otherwise specified), thrombocytopenia, lymphopenia, haemorrhage, anaemia, neutropenia. Less frequent: pancytopenia, bone marrow failure, haemolysis.
• Immune system disorders: Frequent: hypersensitivity (not otherwise specified). Less frequency: anaphylactic reaction, anaphylactoid reaction, anaphylactic shock.
• Nervous system disorders: Frequent: headache, insomnia, 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, QT prolongation. Less frequent: pericardial effusion, myocardial infarction, cardiac failure, tachycardia. Frequency unknown: atrial fibrillation.
• Vascular disorders: Frequency: 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.
• Gastrointestinal disorders: Frequent: nausea, vomiting, diarrhoea, constipation, stomatitis. Less frequent: haemorrhagic oesophagitis, gastrointestinal haemorrhage.
• Hepatobiliary disorders: Less frequent: hepatic failure.
• Skin and subcutaneous tissue disorders: Frequent: alopecia, skin disorders (not otherwise specified), urticaria. Less frequent: erythema, dermatitis, pruritus, maculopapular rash, hyperhidrosis. Frequency unknown: Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) (combination therapy with rituximab).
• 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: multi-organ failure.
• Investigations: Frequent: decreased: haemoglobin; increased: creatinine, urea, AST, ALT, alkaline phosphatase, bilirubin, hypokalemia.

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on the SAHPRA website.

After application of a 30 minute infusion of BAXIMO 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/mu00b2. The dose limiting toxicity was grade 4 thrombocytopenia. Cardiac toxicity was not dose limiting with this schedule. 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 counter measures to control haematological side effects.

Bendamustine hydrochloride, as in BAXIMO, and its metabolites are dialysable to a small extent.