RIXATHON CONCENTRATE FOR SOLUTION FOR INFUSION 500MG/50ML

INFUSION, SOLUTION CONCENTRATE

**4.2 Posology and method of administration** **4.2.1 Standard Dosage** Route of administration Intravenous (IV) infusion. RIXATHON should be administered as an IV infusion through a dedicated line, in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced physician. The prepared infusion solution must not be administered as an IV injection bolus or push. _Premedication and Prophylactic Medications_ Premedication consisting of an analgesic/antipyretic (e.g., paracetamol) and an antihistaminic drug (e.g., diphenhydramine) should always be administered before each infusion of RIXATHON. Premedication with corticosteroids should be considered if rituximab is not given in combination with glucocorticoid-containing chemotherapy for treatment of non-Hodgkin’s lymphoma. Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4 – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). Patients who develop evidence of severe reactions, especially severe dyspnea, bronchospasm and hypoxia should have the infusion interrupted immediately. The patient should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest x-ray. The infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest x-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time the decision to stop the treatment should be seriously considered on a case-by-case basis. Mild or moderate infusion-related reactions (see section 4.8 – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms. Rixathon is not interchangeable or substitutable with other preparation of rituximab products. **Low-grade or follicular non-Hodgkin’s lymphoma** _Initial treatment_ - _Intravenous monotherapy_ The recommended dosage of RIXATHON used as monotherapy for adult patients is 375 mg/m2 body surface area, administered as an IV infusion once weekly for 4 weeks. - _Intravenous combination therapy_ The recommended dosage of RIXATHON in combination with CVP chemotherapy is 375 mg/m2 body surface area for 8 cycles (21 days/cycle), administered on day 1 of each chemotherapy cycle after IV administration of the corticosteroid component of CVP. RIXATHON has shown acceptable safety in combination with other chemotherapies e.g., CHOP. _Re-treatment following relapse_ Patients who have responded to RIXATHON initially have been treated again with RIXATHON at a dose of 375 mg/m2 body surface area, administered as an IV infusion once weekly for 4 weeks (see _Re-treatment, weekly for 4 doses_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). _Maintenance treatment_ Previously untreated follicular lymphoma The recommended dose of RIXATHON used as a maintenance treatment for patients with previously untreated follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface area once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum period of two years. Relapsed/refractory follicular lymphoma Patients who have responded to induction treatment may receive maintenance therapy with RIXATHON given at 375 mg/m2 body surface area once every 3 months until disease progression or for a maximum period of two years. **Diffuse large B-cell non-Hodgkin’s lymphoma** RIXATHON should be used in combination with CHOP chemotherapy. The recommended dosage of RIXATHON is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle after IV administration of the corticosteroid component of CHOP. The other components of CHOP (cyclophosphamide, doxorubicin and vincristine) should be given after the administration of RIXATHON. Safety and efficacy of RIXATHON have not been established in combination with other chemotherapies. **Chronic Lymphocytic Leukaemia** Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are > 25 x109/L it is recommended to administer prednisone/prednisolone 100 mg IV shortly before infusion with RIXATHON to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome. The dose of RIXATHON for CLL is 375 mg/m2 in the first cycle and 500 mg/m2 in cycles 2–6, in combination with FC, administered every 28 days _(see “Intravenous Formulation Infusion Rate”)_. **Rheumatoid arthritis** A course of RIXATHON consists of two 1000 mg IV infusions. The recommended dosage of RIXATHON is 1000 mg by IV infusion followed two weeks later by the second 1000 mg IV infusion _(see “Intravenous Formulation Infusion Rate”)_. Patients may receive further courses of treatment, based on signs and symptoms of disease. In clinical studies, no patient received a second course of rituximab treatment within 16 weeks of the first infusion of the first course. The time interval between courses was variable, with the majority of patients receiving further therapy 6–12 months after the previous course. Some patients required even less frequent retreatment. The efficacy and safety of further courses is comparable to the first course (see sections 4.8, Experience from Rheumatoid Arthritis and section 5.1.2 Clinical/Efficacy Studies, Chronic lymphocytic leukemia – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). Rheumatoid arthritis patients should receive treatment with 100 mg IV methylprednisolone 30 minutes prior to RIXATHON to decrease the rate and severity of acute infusion reactions (see section 4.4 – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). _**Rheumatoid Arthritis Only**_ _Alternative subsequent, faster, infusions schedule:_ In RA, with a dose of 1000 mg RIXATHON, if there are no infusion related reactions or other reasons to slow or cease the infusion, the standard infusion schedules shown above result in an estimated duration of infusion of 4h 15 minutes for the first infusion and 3h 15 minutes for the second infusion in each course. If patients did not experience a serious infusion-related adverse event with their first or subsequent infusions of a dose of 1000 mg RIXATHON administered over the standard infusion schedule, a more rapid infusion can be administered for second and subsequent infusions using the same concentration as in previous infusions (4 mg/ml in a 250 ml volume). Initiate at a rate of 250mg/hour for the first 30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this infusion schedule can be used when administering subsequent infusions. With this infusion schedule, the 1000 mg/250 ml infusion will generally be completed in 2 h. Patients who have clinically significant cardiovascular disease including arrhythmias or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion. **Intravenous Formulation Infusion Rate** _First intravenous infusion_ The recommended initial infusion rate is 50 mg/h; subsequently, the rate can be escalated in 50 mg/h increments every 30 minutes to a maximum of 400 mg/h. _Subsequent intravenous infusions_ Subsequent infusions of RIXATHON can be started at a rate of 100 mg/h and increased by 100 mg/h increments every 30 minutes to a maximum of 400 mg/h. _Dosage adjustments during treatment_ No dose reductions of RIXATHON are recommended. When RIXATHON is given in combination with CVP chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied. **Special Dosage Instructions** _Pediatric use_ The safety and efficacy of RIXATHON in children and adolescents (<18 years) have not been established. Hypogammaglobulinaemia has been observed in pediatric patients treated with RIXATHON, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long term B-cell depletion in pediatric patients are unknown. _Geriatric use_ No dose adjustment is required in patients aged ≥65 years of age. _Renal Impairment_ The safety and efficacy of renal impairment in rituximab patients has not been established. _Hepatic Impairment_ The safety and efficacy of hepatic impairment in rituximab patients has not been established.