Ibozard 25 Mg/100 Mg Solution

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.

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 10 9 /L or < 75 x 10 9 /L, respectively (see section 4.3).

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

Combination treatment for first-line indolent non-Hodgkinu2019s lymphoma 90 mg/m 2 body surface area IBOZARD on days 1 and 2 in combination with 375 mg/m 2 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/m 2 body surface area IBOZARD on days 1 and 2; every 3 weeks.

Multiple Myeloma 120-150 mg/m 2 body surface area IBOZARD on days 1 and 2, 60 mg/m2 body surface area prednisone i.v. 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 10 9 / L or u2264 75 x 10 9 / L , respectively. Treatment can be continued after leukocyte values have increased to > 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 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 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 Method of administration).

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.

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

Paediatric patients There is no experience in children and adolescents with IBOZARD.

Method of administration The solution is administered by intravenous infusion over 30 - 60 min. 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 the bendamustine hydrochloride or to any of the excipients in IBOZARD (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)] 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 IBOZARD 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). Treatment with IBOZARD 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 are more pronounced when bendamustine hydrochloride as IBOZARD is combined with rituximab. Patients with lymphopenia and low CD4-positive T-cell count following treatment with IBOZARD 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 IBOZARD 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 may occur after these patients received bendamustine hydrochloride as in IBOZARD. 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 IBOZARD 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 Medicine 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 medical practitioner and should be told to seek medical attention immediately if they develop these symptoms. Some events occurred when IBOZARD 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, IBOZARD should be withheld or discontinued. For severe skin reactions with suspected relationship to bendamustine hydrochloride as IBOZARD, treatment should be discontinued.

Cardiac disorders During treatment with IBOZARD 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 IBOZARD 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 IBOZARD treatment. The onset tends to be within 48 hours of the first dose of IBOZARD 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 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 IBOZARD have been reported. 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. IBOZARD should be discontinued.

Contraception IBOZARD 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 IBOZARD 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, tumour lysis syndrome and anaphylaxis. There have been reports of secondary tumours, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukaemia and bronchial carcinoma. IBOZARD contains mannitol, should not take IBOZARD people who are allergic to mannitol.

No in - vivo interaction studies have been performed. When IBOZARD is combined with myelosuppressive medicines, the effect of IBOZARD 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 IBOZARD. Combination of IBOZARD with ciclosporine 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 as in IBOZARD metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme (see section 5.2). Therefore, the potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir and cimetidine exist.

Fertility Women of childbearing potential must use effective methods of contraception both before and during IBOZARD therapy. Men being treated with IBOZARD 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 IBOZARD.

Pregnancy There are insufficient data from the use of IBOZARD in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo-/fetolethal, teratogenic and genotoxic. Therefore, IBOZARD is contraindicated during pregnancy. The mother should be informed about the risk to the foetus. 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.

Breast - feeding It is not known whether Bendamustine passes into the breast milk, therefore, IBOZARD is contraindicated during breast feeding (see section 4.3). Breast feeding must be discontinued during treatment with IBOZARD.

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

a. Summary of the safety profile The most common adverse reactions with IBOZARD are hematological adverse reactions (leukopenia, thrombopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting).

Tabulated list of adverse reactions For patients who received only IBOZARD, the following adverse reactions were reported during therapy plus follow-up for 14 days after treatment was stopped:

b. Tabulated list of adverse reactions

S YSTEM ORGAN CLASS FREQUENCY

After application of a 30 min infusion of IBOZARD 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 IBOZARD at day 1 and 2 every 3 weeks the MTD was found to be 180 mg/m 2 . The dose limiting toxicity was grade 4 thrombocytopenia. Cardiac toxicity was not dose limiting with this schedule.

Treatment 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. IBOZARD and its metabolites are dialyzable to a small extent.