RIXATHON CONCENTRATE FOR SOLUTION FOR INFUSION 500MG/50ML [SIN15969P]

Product Info

RIXATHON CONCENTRATE FOR SOLUTION FOR INFUSION 500MG/50ML

[SIN15969P]

4.1 Therapeutic indications
Non-Hodgkin’s Lymphoma
RIXATHON is indicated for the treatment of patients with relapsed or chemoresistant indolent B-cell non-Hodgkin’s lymphomas.

RIXATHON is indicated for the treatment of patients with CD20 positive diffuse large B-cell non-Hodgkin’s lymphoma (DLCL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy.

RIXATHON is indicated for the treatment of previously untreated patients with stage III–IV follicular lymphoma in combination with CVP chemotherapy.

RIXATHON maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.

Chronic Lymphocytic Leukaemia
RIXATHON is indicated in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.

Rheumatoid Arthritis
RIXATHON in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitor therapies.

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 also be considered.

Premedication with glucocorticoids should be considered if rituximab is not given in combination with glucocorticoid-containing chemotherapy for treatment of non-Hodgkin’s lymphoma.

For adult Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukaemia patients administered RIXATHON according to the 90-minute infusion rate, premedication with glucocorticoids should be considered if RIXATHON is not given in combination with glucocorticoid-containing chemotherapy.

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.

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.

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 recommended dosage 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).

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.

Adult patients – Non-Hodgkin’s lymphoma and Chronic lymphocytic leukaemia Only:
If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen. Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8).
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.

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.

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.

4.3 Contraindications
Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information.

Active, severe infections (see section 4.4 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Patients in a severely immunocompromised state.