MABTHERA CONCENTRATE FOR SOLUTION FOR INFUSION 500 MG/50ML [SIN09946P]

Product Info

MABTHERA CONCENTRATE FOR SOLUTION FOR INFUSION 500 MG/50ML

[SIN09946P]

2.1 Therapeutic Indication(s)
MabThera IV and MabThera SC
Non-Hodgkin’s Lymphoma:
MabThera IV and MabThera SC are 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.

• previously untreated patients with stage III–IV follicular lymphoma in combination with CVP chemotherapy.

MabThera IV and MabThera SC maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.

MabThera IV only
Non-Hodgkin’s Lymphoma:
MabThera IV is indicated for the treatment of patients with relapsed or chemoresistant indolent B-cell non-Hodgkin’s lymphomas.

Chronic Lymphocytic Leukaemia:
MabThera IV 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:
MabThera IV 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.

2.2 Dosage and Administration
General
Intravenous and Subcutaneous Formulations
Substitution by any other biological medicinal product requires the consent of the prescribing physician.

It is important to check the medicinal product labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and strength is being given to the patient, as prescribed.

MabThera should always be administered in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced physician.

The safety and efficacy of alternating or switching between MabThera and products that are biosimilar but not deemed interchangeable to MabThera has not been established. Therefore, the benefit/risk of alternating or switching need to be carefully considered.

Premedication and Prophylactic Medications:
Premedication consisting of an analgesic/anti-pyretic (e.g. paracetamol) and an antihistaminic drug (e.g. diphenhydramine), should always be given before each administration of MabThera. Premedication with corticosteroids should also be considered.

Premedication with glucocorticoids should be considered if MabThera 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 2.4 Warnings and Precautions – 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 2.6 Undesirable effects – 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 MabThera are recommended. When MabThera is given in combination with CVP chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

Intravenous Formulation
MabThera IV formulation is not intended for subcutaneous administration (see section 4.2 Special Instructions for Use, Handling and Disposal – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

MabThera should be administered as an IV infusion through a dedicated line. The prepared infusion solution must not be administered as an IV injection or bolus 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 MabThera IV 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.

Subcutaneous Formulation
MabThera SC formulation is not intended for intravenous administration and should be given via subcutaneous injection only (see section 4.2 Special Instructions for Use, Handling and Disposal – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

The 1400 mg strength is intended for subcutaneous use in non-Hodgkin’s lymphoma (NHL) only.

MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall and never into areas where the skin is red, bruised, tender, hard or areas where there are moles or scars. No data are available on performing the injection in other sites of the body, therefore injections should be restricted to the abdominal wall.

During the treatment course with MabThera subcutaneous formulation, other medicinal products for subcutaneous administration should preferably be given at different sites.

MabThera subcutaneous formulation should be administered as subcutaneous injection only, over approximately 5 minutes. The hypodermic injection needle must only be attached to the syringe immediately prior to administration to avoid potential needle clogging.

If an injection is interrupted it can be resumed at the same site or another location may be used, if appropriate.

Standard dosage
Low-grade or follicular non-Hodgkin’s lymphoma
Intravenous Formulation
Initial treatment:

• Intravenous monotherapy
  The recommended dosage of MabThera IV 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 MabThera IV 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. MabThera has shown acceptable safety in combination with other chemotherapies e.g. CHOP.

Re-treatment following relapse
Patients who have responded to MabThera IV initially have been treated again with MabThera IV 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 MabThera IV 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 MabThera IV given at 375 mg/m² body surface area once every 3 months until disease progression or for a maximum period of two years.

Subcutaneous Formulation
The recommended dose of MabThera subcutaneous formulation used for adult patients is a subcutaneous injection at a fixed dose of 1400 mg irrespective of the patient’s body surface area.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose of MabThera by intravenous infusion, using MabThera intravenous formulation. During their first cycle the patient is at the highest risk of experiencing an infusion/administration related reaction. Beginning therapy with MabThera IV infusion allows management of infusion/administration related reactions by slowing or stopping the intravenous infusion (see section 2.4 Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, they should continue the subsequent cycles with MabThera intravenous formulation until a full intravenous dose is successfully administered.
Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

Initial therapy
The recommended dose of MabThera in combination with chemotherapy for induction treatment of previously untreated or relapsed/ refractory patients with follicular lymphoma is: first cycle with MabThera intravenous formulation 375 mg/m² body surface area, followed by subsequent cycles with MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle. In total: 8 cycles.

MabThera should be administered on day 1 of each chemotherapy cycle, after administration of the glucocorticoid component of the chemotherapy if applicable.

Maintenance therapy

• Previously untreated follicular lymphoma
  The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment for patients with previously untreated follicular lymphoma who have responded to induction treatment is:
  1400 mg 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
  The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment for patients with relapsed/refractory follicular lymphoma who have responded to induction treatment is:
  1400 mg once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum period of two years.

Diffuse Large B-cell Non-Hodgkin’s Lymphoma
Intravenous Formulation
MabThera IV should be used in combination with CHOP chemotherapy. The recommended dosage of MabThera IV 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 MabThera IV. Safety and efficacy of Mabthera have not been established in combination with other chemotherapies.

Subcutaneous Formulation
The recommended dose of MabThera subcutaneous formulation used for adult patients is a subcutaneous injection at a fixed dose of 1400 mg irrespective of the patient’s body surface area.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose of MabThera by intravenous infusion, using MabThera intravenous formulation. During their first cycle the patient is at the highest risk of experiencing an infusion/administration related reaction.

Beginning therapy with MabThera IV infusion allows management of infusion/administration related reactions by slowing or stopping the intravenous infusion (see section 2.4 Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, they should continue the subsequent cycles with MabThera intravenous formulation until a full intravenous dose is successfully administered.
Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

MabThera should be used in combination with CHOP chemotherapy. The recommended dose is: first cycle, MabThera intravenous formulation: 375 mg/m² body surface area, followed by subsequent cycles with MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle. In total: 8 cycles.

MabThera is administered on day 1 of each chemotherapy cycle after intravenous infusion of the glucocorticoid component of CHOP.
Safety and efficacy of MabThera have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin’s lymphoma.

Chronic Lymphocytic Leukaemia
Intravenous Formulation
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 MabThera IV to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dosage of MabThera IV 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” sub-section above).

Rheumatoid arthritis
Intravenous Formulation
A course of MabThera IV consists of two 1000 mg IV infusions. The recommended dosage of MabThera is 1000 mg by IV infusion followed two weeks later by the second 1000 mg IV infusion (see “Intravenous Formulation Infusion Rate” sub-section above).

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 2.6.1 Clinical trials, Experience from Rheumatoid Arthritis and 3.1.2 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 MabThera IV to decrease the rate and severity of acute infusion reactions (see section 2.4 Warnings and Precautions – 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 MabThera IV, 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 MabThera IV 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.

2.2.1 Special Dosage Instructions
Pediatric use:
The safety and efficacy of MabThera in children and adolescents (<18 years) have not been established.
Hypogammaglobulinaemia has been observed in pediatric patients treated with MabThera, 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.

2.3 Contraindications
MabThera is contraindicated in patients with known hypersensitivity to rituximab, to any of its excipients or to murine proteins.

Active, severe infections (see section 2.4 Warnings and Precautions – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Patients in a severely immunocompromised state.