Posology : מינונים

4.2   Posology and method of administration

Rixathon should be administered under the close supervision of an experienced healthcare professional, and in an environment where full resuscitation facilities are immediately available (see section 4.4).

Premedication and prophylactic medications

Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be given before each administration of Rixathon.

In patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia, premedication with glucocorticoids should be considered if Rixathon is not given in combination with glucocorticoid- containing chemotherapy.

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 x 109/L it is recommended to administer prednisone/prednisolone 100 mg intravenous shortly before infusion with Rixathon to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

In patients with rheumatoid arthritis or pemphigus vulgaris, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to Rixathon infusions to decrease the incidence and severity of infusion related reactions (IRRs).

In patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of Rixathon (the last dose of methylprednisolone may be given on the same day as the first infusion of Rixathon). This should be followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered as rapidly as possible based on clinical need) during and after Rixathon treatment.

Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for patients with GPA/MPA or PV during and following Rixathon treatment, as appropriate according to local clinical practice guidelines.

Posology Non-Hodgkin’s lymphoma

Follicular non-Hodgkin's lymphoma
Combination therapy
The recommended dose of Rixathon in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular lymphoma is: 375 mg/m2 body surface area per cycle, for up to 8 cycles.

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

Maintenance therapy
• 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
The recommended dose of Rixathon used as a maintenance treatment for patients with relapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface area 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.

Monotherapy
• Relapsed/refractory follicular lymphoma
The recommended dose of Rixathon monotherapy used as induction treatment for adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks.

For retreatment with Rixathon monotherapy for patients who have responded to previous treatment with rituximab monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks (see section 5.1).

Diffuse large B cell non-Hodgkin's lymphoma

Rixathon should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of rituximab have not been established in combination with other chemotherapies in diffuse large B cell non- Hodgkin’s lymphoma.

Dose adjustments during treatment

No dose reductions of Rixathon are recommended. When Rixathon is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.
Chronic lymphocytic leukaemia

The recommended dosage of Rixathon in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m2 body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after Rixathon infusion.

Rheumatoid arthritis
A course of Rixathon consists of two 1000 mg intravenous infusions. The recommended dosage of Rixathon is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later.

Subsequent courses should be administrated every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.

Available data suggest that clinical response is usually achieved within 16 - 24 weeks of an initial treatment course. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Granulomatosis with polyangiitis and microscopic polyangiitis

The recommended dosage of Rixathon for induction of remission therapy of granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (four infusions in total).


Pemphigus vulgaris
The recommended dosage of Rixathon for the treatment of pemphigus vulgaris is 1000 mg administered as an IV infusion followed two weeks later by a second 1000 mg IV infusion in combination with a tapering course of glucocorticoids.


Maintenance treatment
A maintenance infusion of 500 mg IV should be administered at month 12 and then every 6 months thereafter based on clinical evaluation.


Treatment of relapse
In the event of relapse, patients may receive 1000 mg IV. The healthcare provider should also consider resuming or increasing the patient’s glucocorticoid dose based on clinical evaluation.
Subsequent infusions may be administered no sooner than 16 weeks following the previous infusion.

Special populations

Paediatric population
The safety and efficacy of rituximab in children below 18 years has not been established. No data are available.

Elderly
No dose adjustment is required in elderly patients (aged >65 years).

Method of administration
Rixathon is for intravenous use. The prepared Rixathon solution should be administered as an intravenous infusion through a dedicated line. It should not be administered as an intravenous push or bolus.
Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4).
Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. In all patients, 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 (IRR) (section 4.8) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.

First infusion

The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.


Subsequent infusions
All indications
Subsequent doses of Rixathon can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h.

Rheumatoid arthritis only

Alternative subsequent, faster, infusion schedule
If patients did not experience a serious infusion related reaction 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.

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.