TRUXIMA Concentrate for solution for infusion Ref.[7416] Active ingredients: Rituximab

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

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

In patients with rheumatoid arthritis, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to Truxima 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 Truxima (the last dose of methylprednisolone may be given on the same day as the first infusion of Truxima). 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 Truxima treatment.

Posology

Non-Hodgkin’s lymphoma

Follicular non-Hodgkin’s lymphoma

Combination therapy:

The recommended dose of Truxima in combination with chemotherapy for induction treatment of previously untreated or relapsed/ refractory patients with follicular lymphoma is: 375 mg/m 2 body surface area per cycle, for up to 8 cycles. Truxima 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 Truxima 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 Truxima 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 Truxima 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/m 2 body surface area, administered as an intravenous infusion once weekly for four weeks.

For retreatment with Truxima monotherapy for patients who have responded to previous treatment with Truxima 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

Truxima 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 Truxima 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 Truxima are recommended. When Truxima is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

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

The recommended dosage of Truxima 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 Truxima infusion.

Rheumatoid arthritis

Patients treated with Truxima must be given the patient alert card with each infusion. A course of Truxima consists of two 1000 mg intravenous infusions. The recommended dosage of Truxima is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later.

The need for further courses should be evaluated 24 weeks following the previous course. Retreatment should be given at that time if residual disease activity remains, otherwise retreatment should be delayed until disease activity returns.

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

Patients treated with Truxima must be given the patient alert card with each infusion.

The recommended dosage of Truxima for induction of remission therapy of granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m 2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (four infusions in total).

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with granulomatosis with polyangiitis or microscopic polyangiitis during and following Truxima treatment, as appropriate.

Special populations

Elderly

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

Paediatric population

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

Method of administration

The prepared Truxima 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 (IRRs) (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 Truxima 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 Truxima 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.

Limited experience with doses higher than the approved dose of intravenous rituximab formulation is available from clinical trials in humans. The highest intravenous dose of rituximab tested in humans to date is 5000 mg (2250 mg/m²), tested in a dose escalation study in patients with CLL. No additional safety signals were identified.

Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.

In the post-marketing setting five cases of rituximab overdose have been reported. Three cases had no reported adverse event. The two adverse events that were reported were flu-like symptoms, with a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

Unopened vial: 3 years.

Diluted product:

The prepared infusion solution of rituximab in 0.9% sodium chloride solution is physically and chemically stable for 30 days at 2°C-8°C and subsequently 24 hours at room temperature (not more than 30°C). The prepared infusion solution of rituximab in 5% glucose solution is physically and chemically stable for 24 hours at 2°C-8°C and subsequently 12 hours at room temperature (not more than 30°C).

From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C–8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C–8°C). Keep the container in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10 mL. Pack of 2 vials.

Truxima is provided in sterile, preservative-free, non-pyrogenic, single use vials.

Aseptically withdraw the necessary amount of Truxima, and dilute to a calculated concentration of 1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/mL (0.9%) solution for injection or 5% D-Glucose in water. For mixing the solution, gently invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.