RITEMVIA Concentrate for solution for infusion Ref.[50424] Active ingredients: Rituximab

Ritemvia 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 Ritemvia.

In adult patients with non-Hodgkin’s lymphoma, premedication with glucocorticoids should be considered if Ritemvia 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 Ritemvia. In addition, prednisone should be given as indicated in Table 1.

In patients with GPA or MPA in disease remission or pemphigus vulgaris, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to each infusion of Ritemvia 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 Ritemvia (the last dose of methylprednisolone may be given on the same day as the first infusion of Ritemvia). 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 Ritemvia treatment.

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

Paediatric population

In paediatric patients with GPA or MPA, prior to the first Ritemvia 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 Ritemvia 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 Ritemvia treatment, as appropriate.

Posology

Non-Hodgkin’s lymphoma

Follicular non-Hodgkin’s lymphoma

Combination therapy:

The recommended dose of Ritemvia 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.

Ritemvia 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 Ritemvia 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 Ritemvia 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 Ritemvia 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 Ritemvia monotherapy for patients who have responded to previous treatment with Ritemvia 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:

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

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

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

Adult induction of remission

The recommended dosage of Ritemvia 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 Ritemvia, maintenance treatment in adult patients with GPA and MPA should be initiated no sooner than 16 weeks after the last Ritemvia infusion.

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

Ritemvia 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 Ritemvia 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 Ritemvia maintenance therapy, up to 5 years.

Pemphigus vulgaris

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

The recommended dosage of Ritemvia 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

Elderly

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

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, Ritemvia should be used in combination with systemic Lymphome Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dosage of Ritemvia is 375 mg/m² BSA, administered as an intravenous infusion. No Ritemvia dose adjustments, other than by BSA, are required.

The safety and efficacy of Ritemvia 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.

Ritemvia 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 Ritemvia 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 Ritemvia:

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 Ritemvia 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 Ritemvia in paediatric patients (≥2 to <18 years of age) has not been established in indications other than severe, active GPA or MPA.

Ritemvia 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).

Method of administration

The prepared Ritemvia 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 Ritemvia can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h increments at 30minute intervals, to a maximum of 400 mg/h.

Paediatric patients – non-Hodgkin’s lymphoma

First infusion:

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

Subsequent infusions:

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

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:

4 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 vial in the outer carton in order to protect from light.

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

Ritemvia 100 mg concentrate for solution for infusion: Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10 mL. Pack of 2 vials.

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

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

Aseptically withdraw the necessary amount of Ritemvia, 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.