RUXIENCE Concentrate for solution for infusion Ref.[10654] Active ingredients: Rituximab

Ruxience 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 Ruxience.

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

In paediatric patients with non-Hodgkin’s lymphoma, premedication with paracetamol and H1 antihistamine (= diphenhydramine or equivalent) should be administered 30 to 60 minutes before the start of the infusion of Ruxience. In addition, prednisone should be given as indicated in Table 1.

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 Ruxience to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

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

In adult patients with GPA or MPA, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of Ruxience (the last dose of methylprednisolone may be given on the same day as the first infusion of Ruxience). 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 the 4 week induction course of Ruxience treatment.

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

Paediatric population

In paediatric patients with GPA or MPA, prior to the first Ruxience IV infusion, methylprednisolone should be given IV for three daily doses of 30 mg/kg/day (not to exceed 1 g/day) to treat severe vasculitis symptoms. Up to three additional daily doses of 30 mg/kg IV methylprednisolone can be given prior to the first Ruxience infusion.

Following completion of IV methylprednisolone administration, patients should receive oral prednisone 1 mg/kg/day (not to exceed 60 mg/day) and tapered as rapidly as possible per clinical need (see section 5.1).

Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for paediatric patients with GPA or MPA during and following Ruxience treatment, as appropriate.

Posology

It is important to check the medicinal product labels to ensure that the appropriate formulation is being given to the patient, as prescribed.

Non-Hodgkin’s lymphoma

Follicular non-Hodgkin’s lymphoma

Combination therapy:

The recommended dose of Ruxience 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.

Ruxience 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 Ruxience 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 (12 infusions in total).

• Relapsed/refractory follicular lymphoma

The recommended dose of Ruxience 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 (8 infusions in total).

Monotherapy:

• Relapsed/refractory follicular lymphoma

The recommended dose of Ruxience 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 re-treatment with Ruxience 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).

Adult diffuse large B cell non-Hodgkin’s lymphoma

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

Chronic lymphocytic leukaemia

The recommended dosage of Ruxience 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 Ruxience infusion.

Rheumatoid arthritis

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

A course of Ruxience consists of two 1000 mg intravenous infusions. The recommended dosage of Ruxience 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. Re-treatment should be given at that time if residual disease activity remains, otherwise re-treatment 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 (GPA) and microscopic polyangiitis (MPA)

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

Adult induction of remission

The recommended dosage of Ruxience for induction of remission therapy in adult patients with GPA and MPA is 375 mg/m² body surface area, administered as an intravenous infusion once weekly for 4 weeks (four infusions in total).

Adult maintenance treatment

Following induction of remission with Ruxience, maintenance treatment in adult patients with GPA and MPA should be initiated no sooner than 16 weeks after the last Ruxience infusion.

Following induction of remission with other standard of care immunosuppressants, Ruxience maintenance treatment should be initiated during the 4 week period that follows disease remission.

Ruxience should be administered as two 500 mg IV infusions separated by two weeks, followed by a 500 mg IV infusion every 6 months thereafter. Patients should receive Ruxience for at least 24 months after achievement of remission (absence of clinical signs and symptoms). For patients who may be at higher risk for relapse, physicians should consider a longer duration of Ruxience maintenance therapy, up to 5 years.

Pemphigus vulgaris

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

The recommended dosage of Ruxience 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 months 12 and 18, and then every 6 months thereafter if needed, 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

Non-Hodgkin’s lymphoma

In paediatric patients from ≥6 months to <18 years of age with previously untreated, advanced stage CD20 positive DLBCL/BL/BAL/BLL, Ruxience should be used in combination with systemic Lymphome Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dosage of Ruxience is 375 mg/m² BSA, administered as an IV infusion. No Ruxience dose adjustments, other than by BSA, are required.

The safety and efficacy of rituximab in paediatric patients ≥ 6 months to < 18 years of age has not been established in indications other than previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL. Only limited data are available for patients under 3 years of age. See section 5.1 for further information.

Ruxience should not be used in paediatric patients from birth to < 6 months of age with CD20 positive diffuse large B-cell lymphoma (see section 5.1).

Table 1. Posology of Ruxience administration for Non-Hodgkin’s lymphoma paediatric patients:

ANC = Absolute Neutrophil Count; COP = Cyclophosphamide, Vincristine, Prednisone; COPDAM = Cyclophosphamide, Vincristine, Prednisolone, Doxorubicin, Methotrexate; CYM = CYtarabine (Aracytine, Ara-C), Methotrexate; CYVE = CYtarabine (Aracytine, Ara-C), VEposide (VP16)

Table 2. Treatment plan for Non-Hodgkin’s lymphoma paediatric patients: Concomitant chemotherapy with Ruxience:

Consecutive courses should be given as soon as blood count recovery and patient’s condition allows except for the maintenance courses which are given at 28 day intervals
BAL = Burkitt leukaemia (mature B-cell acute leukaemia); CSF = Cerebrospinal Fluid; CNS = Central Nervous System; HDMTX = High-dose Methotrexate; LDH = Lactic Acid Dehydrogenase

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)

Induction of remission:

The recommended dosage of Ruxience for induction of remission therapy in paediatric patients with severe, active GPA or MPA is 375 mg/m² BSA, administered as an IV infusion once weekly for 4 weeks.

The safety and efficacy of rituximab in paediatric patients (≥2 to <18 years of age) has not been established in indications other than severe, active GPA or MPA. Ruxience should not be used in paediatric patients less than 2 years of age with severe, active GPA or MPA as there is a possibility of an inadequate immune response towards childhood vaccinations against common, vaccine preventable childhood diseases (e.g. measles, mumps, rubella, and poliomyelitis) (see section 5.1).

Elderly

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

Method of administration

The prepared Ruxience 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) (see 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/hour; after the first 30 minutes, it can be escalated in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.

Subsequent infusions

All indications

Subsequent doses of Ruxience can be infused at an initial rate of 100 mg/hour, and increased by 100 mg/hour increments at 30 minute intervals, to a maximum of 400 mg/hour.

Paediatric patients – non-Hodgkin’s lymphoma

First infusion:

The recommended initial rate for infusion is 0.5 mg/kg/hour (maximum 50 mg/hour); it can be escalated by 0.5 mg/kg/hour every 30 minutes if there is no hypersensitivity or infusion-related reactions, to a maximum of 400 mg/hour.

Subsequent infusions:

Subsequent doses of Ruxience can be infused at an initial rate of 1 mg/kg/hour (maximum 50 mg/hour); it can be increased by 1 mg/kg/hour every 30 minutes to a maximum of 400 mg/hour.

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 Ruxience 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 250 mg/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: 24 months.

Diluted medicinal product:

• After aseptic dilution in sodium chloride solution:
  The prepared infusion solution of Ruxience in 0.9% sodium chloride solution is physically and

chemically stable for 35 days at 2°C–8°C plus an additional 24 hours at ≤30°C.

• After aseptic dilution in D-glucose solution:
  The prepared infusion solution of Ruxience in 5% D-glucose solution is physically and chemically

stable for 24 hours at 2°C–8°C plus an additional 24 hours at ≤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

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.

Ruxience 100 mg concentrate for solution for infusion: Clear Type I glass vials with chlorobutyl rubber stopper containing 100 mg of rituximab in 10 mL. Pack of 1 vial.

Ruxience 500 mg concentrate for solution for infusion: Clear Type I glass vials with chlorobutyl rubber stopper containing 500 mg of rituximab in 50 mL. Pack of 1 vial.

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

Aseptically withdraw the necessary amount of Ruxience 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.