RIXATHON 500mg perfusive solution concentrate medication leaflet

Each mL contains 10 mg of rituximab.

Each 10 mL vial contains 100 mg of rituximab.

Each mL contains 10 mg of rituximab.

Each 50 mL vial contains 500 mg of rituximab.

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing aglycosylated immunoglobulin with human IgG1 constant regions and murine light-chain andheavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamsterovary) cell suspension culture and purified by affinity chromatography and ion exchange, includingspecific viral inactivation and removal procedures.

Each 10 mL vial contains 2.3 mmol (52.6 mg) sodium.

Each 50 mL vial contains 11.5 mmol (263.2 mg) sodium.

Each 10 mL vial contains 7.0 mg of polysorbate 80 (E 433).

Each 50 mL vial contains 35.0 mg of polysorbate 80 (E 433).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless to slightly yellowish liquid with pH of 6.3 - 6.7 and osmolality of ≥ 240 mOsm/kg.

Rixathon is indicated for the treatment of previously untreated adult patients with stage III-IVfollicular lymphoma in combination with chemotherapy.

Rixathon maintenance therapy is indicated for the treatment of adult follicular lymphoma patientsresponding to induction therapy.

Rixathon monotherapy is indicated for treatment of adult patients with stage III-IV follicularlymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.

Rixathon is indicated for the treatment of adult patients with CD20 positive diffuse large B-cell non-

Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine,prednisolone) chemotherapy.

Rixathon in combination with chemotherapy is indicated for the treatment of paediatric patients(aged 6 months to less than 18 years old) with previously untreated advanced stage CD20 positivediffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL)/Burkitt leukaemia (mature B-cellacute leukaemia) (BAL) or Burkitt-like lymphoma (BLL).

Rixathon in combination with chemotherapy is indicated for the treatment of adult patients withpreviously untreated and relapsed/refractory CLL. Only limited data are available on efficacy andsafety for patients previously treated with monoclonal antibodies including rituximab or patientsrefractory to previous rituximab plus chemotherapy.

See section 5.1 for further information.

Rixathon in combination with methotrexate is indicated for the treatment of adult patients with severeactive rheumatoid arthritis who have had an inadequate response or intolerance to otherdisease-modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor(TNF) inhibitor therapies.

Rituximab has been shown to reduce the rate of progression of joint damage as measured by X-ray andto improve physical function, when given in combination with methotrexate.

Rixathon, in combination with glucocorticoids, is indicated for the treatment of adult patients withsevere, active GPA (Wegener’s) and MPA.

Rixathon, in combination with glucocorticoids, is indicated for the induction of remission in paediatricpatients (aged 2 to less than 18 years old) with severe, active GPA (Wegener’s) and MPA.

Rixathon is indicated for the treatment of adult patients with moderate to severe PV.

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

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

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

In adult patients with NHL and CLL, premedication with glucocorticoids should be considered if

Rixathon is not given in combination with glucocorticoid-containing chemotherapy.

For adult NHL and CLL patients administered Rixathon according to the 90-minute infusion rate,premedication with glucocorticoids should be considered if Rixathon is not given in combination withglucocorticoid-containing chemotherapy.

In paediatric patients with NHL, premedication with paracetamol and H1 antihistamine (=diphenhydramine or equivalent) should be administered 30 to 60 minutes before the start of theinfusion of Rixathon. In addition, prednisone should be given as indicated in Table 1.

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to startof therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLLpatients whose lymphocyte counts are > 25 x 109/L, it is recommended to administerprednisone/prednisolone 100 mg intravenous shortly before infusion with Rixathon to decrease therate and severity of acute infusion reactions and/or cytokine release syndrome.

Rheumatoid arthritis, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA),and pemphigus vulgaris

In patients with rheumatoid arthritis, GPA or MPA or PV, premedication with 100 mg intravenousmethylprednisolone should be completed 30 minutes prior to each infusion of Rixathon to decrease theincidence and severity of infusion-related reactions (IRRs).

In adult patients with GPA or MPA methylprednisolone given intravenously for 1 to 3 days at a doseof 1,000 mg per day is recommended prior to the first infusion of Rixathon (the last dose ofmethylprednisolone may be given on the same day as the first infusion of Rixathon). This should befollowed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possiblebased on clinical need) during and after the 4-week induction course of Rixathon treatment.

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

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

Following completion of intravenous methylprednisolone administration, paediatric patients shouldreceive oral prednisone 1 mg/kg/day (not to exceed 60 mg/day) and tapered as rapidly as possible perclinical need (see section 5.1).

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

No dose reductions of Rixathon are recommended. When Rixathon is given in combination withchemotherapy, standard dose reductions for the chemotherapeutic medicinal products should beapplied.

The recommended dose of Rixathon in combination with chemotherapy for induction treatment ofpreviously untreated or relapsed/refractory patients with follicular lymphoma is: 375 mg/m2 bodysurface area per cycle, for up to 8 cycles.

Rixathon should be administered on Day 1 of each chemotherapy cycle, after intravenousadministration of the glucocorticoid component of the chemotherapy if applicable.

* Previously untreated follicular lymphoma

The recommended dose of Rixathon used as a maintenance treatment for patients with previouslyuntreated follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surfacearea once every 2 months (starting 2 months after the last dose of induction therapy) until diseaseprogression or for a maximum period of two years (12 infusions in total).

* Relapsed/refractory follicular lymphoma

The recommended dose of Rixathon used as a maintenance treatment for patients withrelapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m2body surface area once every 3 months (starting 3 months after the last dose of induction therapy) untildisease progression or for a maximum period of two years (8 infusions in total).

Relapsed/refractory follicular lymphoma

The recommended dose of Rixathon monotherapy used as induction treatment for adult patients withstage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapseafter chemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion onceweekly for four weeks.

For retreatment with Rixathon monotherapy for patients who have responded to previous treatmentwith 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

Rixathon should be used in combination with CHOP chemotherapy. The recommended dose is375 mg/m2 body surface area, administered on Day 1 of each chemotherapy cycle for 8 cycles afterintravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of rituximab havenot been established in combination with other chemotherapies in diffuse large B-cell NHL.

The recommended dose of Rixathon in combination with chemotherapy for previously untreated andrelapsed/refractory patients is 375 mg/m2 body surface area administered on Day 0 of the firsttreatment cycle followed by 500 mg/m2 body surface area administered on Day 1 of each subsequentcycle for 6 cycles in total. The chemotherapy should be given after Rixathon infusion.

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

A course of Rixathon consists of two 1,000 mg intravenous infusions. The recommended dose of

Rixathon is 1,000 mg by intravenous infusion followed by a second 1,000 mg intravenous infusiontwo weeks later.

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

Available data suggest that clinical response is usually achieved within 16 to 24 weeks of an initialtreatment course. Continued therapy should be carefully reconsidered in patients who show noevidence of therapeutic benefit within this time period.

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

The recommended dose of Rixathon 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 for4 weeks (four infusions in total).

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

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

Rixathon should be administered as two 500 mg intravenous infusions separated by two weeks,followed by a 500 mg intravenous infusion every 6 months thereafter. Patients should receive

Rixathon for at least 24 months after achievement of remission (absence of clinical signs andsymptoms). For patients who may be at higher risk for relapse, physicians should consider a longerduration of Rixathon maintenance therapy, up to 5 years.

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

The recommended dose of Rixathon for the treatment of PV is 1000 mg administered as anintravenous infusion followed two weeks later by a second 1000 mg intravenous infusion incombination with a tapering course of glucocorticoids.

A maintenance infusion of 500 mg intravenously should be administered at months 12 and 18, andthen every 6 months thereafter if needed, based on clinical evaluation.

Treatment of relapse

In the event of relapse, patients may receive 1000 mg intravenously. The healthcare provider shouldalso 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.

In paediatric patients from 6 months to less than 18 years of age with previously untreated, advancedstage CD20 positive DLBCL/BL/BAL/BLL, Rixathon should be used in combination with systemic

Lymphome Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dose of Rixathonis 375 mg/m2 BSA, administered as an intravenous infusion. No Rixathon dose adjustments, other thanby BSA, are required.

The safety and efficacy of rituximab in paediatric patients aged 6 months to less than 18 years of agehas 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. Seesection 5.1 for further information.

Rixathon should not be used in paediatric patients from birth to 6 months of age with CD20 positivediffuse large B-cell lymphoma (see section 5.1)

Table 1 Posology of rituximab administration for NHL paediatric patients

Cycle Day of treatment Administration details

Prephase (COP) No rituximab given -

Induction course 1 Day -2(COPDAM1) (corresponding to Day 6 During the 1st induction course, prednisone isof the prephase) given as part of the chemotherapy course, and1st rituximab infusion should be administered prior to rituximab.

Day 12nd rituximab infusion Rituximab will be given 48 hours after the firstinfusion of rituximab.

Induction course 2 Day -2(COPDAM2) 3rd rituximab infusion In the 2nd induction course, prednisone is not givenat the time of rituximab administration.

Day 14th rituximab infusion Rituximab will be given 48 hours after the thirdinfusion of rituximab.

Consolidation Day 1course 1 5th rituximab infusion Prednisone is not given at the time of rituximab(CYM/CYVE) administration.

Consolidation Day 1course 2 6th rituximab infusion Prednisone is not given at the time of rituximab(CYM/CYVE) administration.

Maintenance course Day 25 to 28 of1 (M1) consolidation course 2 Starts when peripheral counts have recovered from(CYVE) consolidation course 2 (CYVE) with ANC>

No rituximab given 1.0 x 109/l and platelets > 100 x 109/l

Maintenance course Day 28 of maintenance -2 (M2) course 1 (M1)

No rituximab given

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 NHL paediatric patients: Concomitant chemotherapy withrituximab

Treatment Patient staging Administration detailsplan

Group B Stage III with high LDH level (> N x Prephase followed by 4 courses:

2), 2 induction courses (COPADM) with

Stage IV CNS negative HDMTX 3 g/m2 and 2 consolidationcourses (CYM)

Treatment Patient staging Administration detailsplan

Group C Group C1: Prephase followed by 6 courses:

BAL CNS negative, Stage IV & BAL 2 induction courses (COPADM) with

CNS positive and CSF negative HDMTX 8 g/m², 2 consolidation courses

Group C3: (CYVE) and 2 maintenance courses (M1

BAL CSF positive, Stage IV CSF and M2)positive

Consecutive courses should be given as soon as blood count recovery and patient’s condition allowsexcept 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

The recommended dose of Rixathon for induction of remission therapy in paediatric patients withsevere, active GPA or MPA is 375 mg/m2 BSA, administered as an intravenous infusion once weeklyfor 4 weeks.

The safety and efficacy of Rixathon in paediatric patients aged 2 to less than 18 years has not beenestablished in indications other than severe, active GPA or MPA.

Rixathon 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 vaccinationsagainst common, vaccine preventable childhood diseases (e.g. measles, mumps, rubella, andpoliomyelitis) (see section 5.1).

No dose adjustment is required in patients aged 65 years and above.

Rixathon is for intravenous use. The prepared Rixathon solution should be administered as anintravenous infusion through a dedicated line. It should not be administered as an intravenous push orbolus.

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 orhypoxia should have the infusion interrupted immediately. Patients with NHL should then beevaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, forpulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted untilcomplete 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 thesame severe adverse reactions occur for a second time, the decision to stop the treatment should beseriously considered on a case by case basis.

Mild or moderate infusion-related reactions (IRRs) (section 4.8) usually respond to a reduction in therate of infusion. The infusion rate may be increased upon improvement of symptoms.

Adult non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, pemphigusvulgaris, adult and paediatric granulomatosis with polyangiitis (GPA) and microscopic polyangiitis(MPA)

The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.

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

Non-Hodgkin’s lymphoma -paediatric patients

The recommended initial rate for infusion is 0.5 mg/kg/h (maximum 50 mg/h); it can be escalated by0.5 mg/kg/h every 30 minutes if there is no hypersensitivity or infusion-related reactions, to amaximum of 400 mg/h.

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

Adult patients - Non-Hodgkin’s lymphoma (NHL) and Chronic lymphocytic leukaemia (CLL) only:

If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapyregimen. Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80%of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, thesame rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or8).

Patients who have clinically significant cardiovascular disease, including arrhythmias, or previousserious infusion reactions to any prior biologic therapy or to rituximab, should not be administered themore rapid infusion.

Alternative subsequent, faster, infusion schedule

If patients did not experience a serious infusion related reaction with their first or subsequent infusionsof a dose of 1,000 mg Rixathon administered over the standard infusion schedule, a more rapidinfusion can be administered for second and subsequent infusions using the same concentration as inprevious infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250 mg/hour for the first30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, thisinfusion schedule can be used when administering subsequent infusions.

Patients who have clinically significant cardiovascular disease, including arrhythmias, or previousserious infusion reactions to any prior biologic therapy or to rituximab, should not be administered themore rapid infusion.

Hypersensitivity to the active substance, to murine proteins, or to any of the excipients listed insection 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac diseasefor use in rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis andpemphigus vulgaris only (see section 4.4 regarding other cardiovascular diseases).

In order to improve the traceability of biological medicinal products, the tradename and the batchnumber of the administered product should be clearly recorded.

All patients treated with Rixathon for rheumatoid arthritis, GPA, MPA or PV must be given the patientalert card with each infusion. The alert card contains important safety information for patientsregarding potential increased risk of infections, PML.

Very rare cases of fatal PML have been reported following use of rituximabfor the treatment ofrheumatoid arthritis and autoimmune diseases [including Systemic Lupus Erythematosus (SLE) andvasculitis] and during post-marketing use of rituximab in NHL and CLL (where the majority ofpatients had received rituximab in combination with chemotherapy or as part of haematopoietic stemcell transplant). Patients must be monitored at regular intervals for any new or worsening neurologicalsymptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must besuspended until PML has been excluded. The clinician should evaluate the patient to determine if thesymptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possiblysuggestive of PML. Consultation with a Neurologist should be considered as clinically indicated.

If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinalfluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may notnotice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised toinform their partner or caregivers about their treatment, since they may notice symptoms that thepatient is not aware of.

If a patient develops PML, the dosing of Rixathon must be permanently discontinued. Followingreconstitution of the immune system in immunocompromised patients with PML, stabilisation orimproved outcome has been seen. It remains unknown if early detection of PML and suspension ofrituximab therapy may lead to similar stabilisation or improved outcome.

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/ormyocardial infarction have occurred in patients treated with rituximab. Therefore, patients with ahistory of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely (see infusion-related reactions, below).

Based on the mechanism of action of rituximab and the knowledge that B-cells play an important rolein maintaining normal immune response, patients have an increased risk of infection followingrituximab therapy (see section 5.1). Serious infections, including fatalities, can occur during therapywith rituximab (see section 4.8). Rixathon should not be administered to patients with an active, severeinfection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severelyimmunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians shouldexercise caution when considering the use of Rixathon in patients with a history of recurring orchronic infections or with underlying conditions which may further predispose patients to seriousinfection, e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulinlevels are determined prior to initiating treatment with Rixathon.

Patients reporting signs and symptoms of infection following Rixathon therapy should be promptlyevaluated and treated appropriately. Before giving a subsequent course of Rixathon treatment, patientsshould be re-evaluated for any potential risk for infections.

For information on progressive multifocal leukoencephalopathy (PML) please see PML section above.

Cases of enteroviral meningoencephalitis including fatalities have been reported following use ofrituximab.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in patientsreceiving Rixathon. The majority of these patients were also exposed to cytotoxic chemotherapy.

Limited information from one study in relapsed/refractory CLL patients suggests that rituximabtreatment may also worsen the outcome of primary hepatitis B infections.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatmentwith Rixathon. At minimum this should include HBsAg-status and HBcAb-status. These can becomplemented with other appropriate markers as per local guidelines. Patients with active hepatitis Bdisease should not be treated with Rixathon. Patients with positive hepatitis B serology (either HBsAgor HBcAb) should consult liver disease experts before start of treatment and should be monitored andmanaged following local medical standards to prevent hepatitis B reactivation.

False negative serologic testing of infections

Due to the risk of false negative serologic testing of infections, alternative diagnostic tools should beconsidered in case of patients presenting with symptoms indicative of rare infectious disease e.g. West

Nile virus and neuroborreliosis.

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnsonsyndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event,with a suspected relationship to rituximab, treatment should be permanently discontinued.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Rixathon is associated with infusion-related reactions, which may be related to release of cytokinesand/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable fromacute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome andanaphylactic and hypersensitivity reactions are described below.

Severe infusion-related reactions with fatal outcome have been reported during post-marketing use ofthe Rixathon intravenous formulation, with an onset ranging within 30 minutes to 2 hours after startingthe first Rixathon intravenous infusion. They were characterised by pulmonary events and in somecases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills,rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied bybronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. Thissyndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia,hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactatedehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acuterespiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema,visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiatingthe first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumourinfiltration may be at greater risk of poor outcome and should be treated with increased caution.

Patients who develop severe cytokine release syndrome should have their infusion interruptedimmediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initialimprovement of clinical symptoms may be followed by deterioration, these patients should be closelymonitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out.

Further treatment of patients after complete resolution of signs and symptoms has rarely resulted inrepeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (≥ 25 x 109/L) of circulating malignant cellssuch as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome,should be treated with extreme caution. These patients should be very closely monitored throughoutthe first infusion. Consideration should be given to the use of a reduced infusion rate for the firstinfusion in these patients or a split dosing over two days during the first cycle and any subsequentcycles if the lymphocyte count is still > 25 x 109/L.

Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated with

Rixathon (including cytokine release syndrome accompanied by hypotension and bronchospasm in10% of patients) see section 4.8. These symptoms are usually reversible with interruption of Rixathoninfusion and administration of an anti-pyretic, an antihistaminic and occasionally oxygen, intravenoussaline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome abovefor severe reactions.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenousadministration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivityreactions typically occur within minutes after starting infusion. Medicinal products for the treatment ofhypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids, should beavailable for immediate use in the event of an allergic reaction during administration of Rixathon.

Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokinerelease syndrome (described above). Reactions attributed to hypersensitivity have been reported lessfrequently than those attributed to cytokine release.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonaryoedema and acute reversible thrombocytopenia.

Since hypotension may occur during Rixathon administration, consideration should be given towithholding anti-hypertensive medicines 12 hours prior to the Rixathon infusion.

Although Rixathon is not myelosuppressive in monotherapy, caution should be exercised whenconsidering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L asclinical experience in this population is limited. Rixathon has been used in 21 patients who underwentautologous bone marrow transplantation and other risk groups with a presumable reduced bonemarrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed during

Rixathon therapy.

The safety of immunisation with live viral vaccines, following rituximab therapy has not been studiedfor NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patientstreated with Rixathon may receive non-live vaccinations; however, with non-live vaccines responserates may be reduced. In a non-randomised study, adult patients with relapsed low-grade NHL whoreceived rituximab monotherapy when compared to healthy untreated controls had a lower rate ofresponse to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin(KLH) neoantigen (4% vs. 76% when assessed for > 2-fold increase in antibody titre). For CLLpatients, similar results are assumable considering similarities between both diseases but that has notbeen investigated in clinical trials.

Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza

A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with rituximab.

Only limited data are available for patients under 3 years of age. See section 5.1 for furtherinformation.

Rheumatoid arthritis, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), andpemphigus vulgaris (PV)

The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit riskrelationship has not been established.

Rituximab is associated with IRRs, which may be related to release of cytokines and/or other chemicalmediators.

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials weremild to moderate in severity. The most common symptoms were allergic reactions like headache,pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportionof patients experiencing any infusion reaction was higher following the first infusion than followingthe second infusion of any treatment course. The incidence of IRR decreased with subsequent courses(see section 4.8). The reactions reported were usually reversible with a reduction in rate, orinterruption, of rituximab infusion and administration of an anti-pyretic, an antihistamine, and,occasionally, oxygen, intravenous sodium chloride 9 mg/ml (0.9%) solution for injection orbronchodilators, and glucocorticoids if required. Closely monitor patients with pre-existing cardiacconditions and those who experienced prior cardiopulmonary adverse reactions. Depending on theseverity of the IRR and the required interventions, temporarily or permanently discontinue Rixathon.

In most cases, the infusion can be resumed at a 50% reduction in rate (e.g. from 100 mg/h to 50 mg/h)when symptoms have completely resolved.

Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline),antihistamines and glucocorticoids, should be available for immediate use in the event of an allergicreaction during administration of Rixathon.

There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III)or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence ofpre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has beenobserved, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history,and those who experienced prior cardiopulmonary adverse reactions, the risk of cardiovascularcomplications resulting from infusion reactions should be considered before treatment with Rixathonand patients closely monitored during administration. Since hypotension may occur during rituximabinfusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior tothe Rixathon infusion.

IRRs in patients with GPA, MPA and PV were consistent with those seen for rheumatoid arthritispatients in clinical trials and in the post-marketing setting (see section 4.8).

Measure blood neutrophils prior to each course of Rixathon, and regularly up to 6-months aftercessation of treatment, and upon signs or symptoms of infection (see section 4.8).

Physicians should review the patient’s vaccination status and patients should, if possible, be broughtup-to-date with all immunisations in agreement with current immunisation guidelines prior toinitiating Rixathon therapy. Vaccination should be completed at least 4 weeks prior to firstadministration of Rixathon.

The safety of immunisation with live viral vaccines following rituximab therapy has not been studied.

Therefore, vaccination with live virus vaccines is not recommended whilst on Rixathon or whilstperipherally B-cell depleted.

Patients treated with Rixathon may receive non-live vaccinations; however, response rates to non-livevaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated withrituximab and methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%),reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcalantibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after rituximab ascompared to patients only receiving methotrexate. Should non-live vaccinations be required whilstreceiving rituximab therapy, these should be completed at least 4 weeks prior to commencing the nextcourse of rituximab.

In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, theproportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella,varicella and tetanus toxoid were generally similar to the proportions at baseline.

The concomitant use of Rixathon and anti-rheumatic therapies other than those specified under therheumatoid arthritis indication and posology is not recommended.

There are limited data from clinical trials to fully assess the safety of the sequential use of other

DMARDs (including TNF inhibitors and other biologics) following rituximab (see section 4.5). Theavailable data indicate that the rate of clinically relevant infection is unchanged when such therapiesare used in patients previously treated with rituximab, however patients should be closely observed forsigns of infection if biologic agents and/or DMARDs are used following rituximab therapy.

Immunomodulatory drugs may increase the risk of malignancy. However, available data do notsuggest an increased risk of malignancy for rituximab used in autoimmune indications beyond themalignancy risk already associated with the underlying autoimmune condition.

This medicinal product contains 2.3 mmol (or 52.6 mg) sodium per 10 mL vial and 11.5 mmol (or263.2 mg) sodium per 50 mL vial, equivalent to 2.6% (for 10 mL vial) and 13.2% (for 50 mL vial) ofthe WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 7.0 mg of polysorbate 80 (E 433) per 10 mL vial and 35.0 mg ofpolysorbate 80 (E 433) per 50 mL vial, which is equivalent to 0.7 mg/mL. Polysorbates may causeallergic reactions.

Currently, there are limited data on possible drug interactions with rituximab.

In CLL patients, co-administration with rituximab did not appear to have an effect on thepharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect offludarabine and cyclophosphamide on the pharmacokinetics of rituximab.

Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab inrheumatoid arthritis patients.

Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may haveallergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonalantibodies.

In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic

DMARD following rituximab. In these patients the rate of clinically relevant infection while onrituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatmentwith the biologic DMARD.

Due to the long retention time of rituximab in B-cell depleted patients, women of childbearingpotential should use effective contraceptive methods during and for 12 months following treatmentwith Rixathon.

IgG immunoglobulins are known to cross the placental barrier.

B-cell levels in human neonates following maternal exposure to rituximab have not been studied inclinical trials. There are no adequate and well-controlled data from studies in pregnant women,however transient B-cell depletion and lymphocytopenia have been reported in some infants born tomothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies(see section 5.3). For these reasons Rixathon should not be administered to pregnant women unless thepossible benefit outweighs the potential risk.

Limited data on rituximab excretion into breast milk suggest very low rituximab concentrations inmilk (relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normalgrowth and development up to 2 years. However, as these data are limited and the long-term outcomesof breastfed infants remain unknown, breastfeeding is not recommended while being treated withrituximab and optimally for 6 months following rituximab treatment.

Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

No studies on the effects of rituximab on the ability to drive and use machines have been performed,although the pharmacological activity and adverse reactions reported to date suggest that rituximabwould have no or negligible influence on the ability to drive and use machines.

The overall safety profile of rituximab in non-Hodgkin’s lymphoma and CLL is based on data frompatients from clinical trials and from post-marketing surveillance. These patients were treated eitherwith rituximab monotherapy (as induction treatment or maintenance treatment following inductiontreatment) or in combination with chemotherapy.

The most frequently observed adverse reactions in patients receiving rituximab were IRRs whichoccurred in the majority of patients during the first infusion. The incidence of infusion-relatedsymptoms decreases substantially with subsequent infusions and is less than 1% after eight doses ofrituximab.

Infectious events (predominantly bacterial and viral) occurred in approximately 30-55% of patientsduring clinical trials in patients with NHL and in 30-50% of patients during clinical trials in patientswith CLL.

The most frequently reported or observed serious adverse reactions were:

* IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.

* Infections, see section 4.4.

* Cardiovascular events, see section 4.4.

Other serious adverse reactions reported include hepatitis B reactivation and PML (see section 4.4.)

The frequencies of adverse reactions reported with rituximab alone or in combination withchemotherapy are summarised in Table 3. Frequencies are defined as very common (≥ 1/10), common(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare(< 1/10,000) and not known (cannot be estimated from the available data). Within each frequencygrouping, undesirable effects are presented in order of decreasing seriousness.

The adverse reactions identified only during post-marketing surveillance, and for which a frequencycould not be estimated, are listed under “not known”, see footnotes.

Table 3 Adverse reactions reported in clinical trials or during post-marketing surveillance inpatients with NHL and CLL disease treated with rituximabmonotherapy/maintenance or in combination with chemotherapy

MedDRA

System organ Verycommon Common Uncommon Rare Very rare Not knownclass

Infections and Bacterial Sepsis, Serious viral PML Enteroviralinfestations infections, +pneumonia, infection2, meningoenceviral +febrile infection, pneumocystis phalitis2, 3infections, +herpes zoster, jirovecii+bronchitis +respiratory tractinfection, fungalinfections,infections ofunknownaetiology, +acutebronchitis,+sinusitis, hepatitis

B1

Blood and Neutropenia, Anaemia, Coagulation Transient Latelymphatic leucopenia, +pancytopenia, disorders, increase in neutropenia4system +febrile +granulocytopenia aplastic serum IgMdisorders neutropenia, anaemia, levels4+thrombocyt haemolyticopenia anaemia,lymphadenopathy

Immune Infusion Hypersensitivity Anaphylaxis Tumour Infusion-system related lysis related acutedisorders reactions5, syndrome, reversibleangioedema cytokine thrombocytorelease penia5syndrome5,serumsickness

Metabolism Hyperglycaemia,and nutrition weight decrease,disorders oedema peripheral,face oedema,increased LDH,hypocalcaemia

Psychiatric Depression,disorders nervousness

Nervous Paraesthesia, Dysgeusia Peripheral Cranialsystem hypoaesthesia, neuropathy, neuropathy,disorders agitation, facial nerve loss of otherinsomnia, palsy6 senses6vasodilatation,dizziness, anxiety

Eye disorders Lacrimation Severedisorder, vision loss6conjunctivitis

Ear and Tinnitus, Hearing loss6labyrinth ear paindisorders

MedDRA

System organ Verycommon Common Uncommon Rare Very rare Not knownclass

Cardiac +Myocardial +Left Severe Heartdisorders infarction5, 7, ventricular cardiac failure5, 7arrhythmia, +atrial failure, disorders 5, 7fibrillation, +supraventrictachycardia, ular+cardiac disorder tachycardia,+ventriculartachycardia,+angina,+myocardialischaemia,bradycardia

Vascular Hypertension, Vasculitisdisorders orthostatic (predominathypotension, elyhypotension cutaneous),leukocytoclasticvasculitis

Respiratory, Bronchospasm5, Asthma, Interstitial Respiratory Lungthoracic and respiratory bronchiolitis lung disease8 failure5 infiltrationmediastinal disease, chest pain, obliterans,disorders dyspnoea, lungincreased cough, disorder,rhinitis hypoxia

Gastrointestin Nausea Vomiting, Abdominal Gastro-al disorders diarrhoea, enlargement intestinalabdominal pain, perforation8dysphagia,stomatitis,constipation,dyspepsia,anorexia, throatirritation

Skin and Pruritis, rash, Urticaria, Severesubcutaneous +alopecia sweating, night bullous skintissue sweats, +skin reactions,disorders disorder Stevens-

Johnson

Syndrome,toxicepidermalnecrolysis(Lyell’s

Syndrome)8

Musculoskelet Hypertonia,al and myalgia,connective arthralgia, backtissue pain, neck pain,disorders pain

Renal and Renalurinary failure5disorders

MedDRA

System organ Verycommon Common Uncommon Rare Very rare Not knownclass

General Fever, chills, Tumour pain, Infusion sitedisorders and asthenia, flushing, malaise, painadministration headache cold syndrome,site conditions +fatigue,+shivering, +multi-organ failure5

Investigations Decreased

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for termsmarked with '+' where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria)reactions. Only the highest frequency observed in the trials is reported1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL2 see also section infection below3 observed during post-marketing surveillance4 see also section haematologic adverse reactions below5 see also section infusion-related reactions below. Rarely fatal cases reported6 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion ofrituximab therapy7 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostlyassociated with infusion-related reactions8 includes fatal cases

The following terms have been reported as adverse reactions during clinical trials, however, werereported at a similar or lower incidence in the rituximab arms compared to control arms:haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% ofpatients in clinical trials, and were predominantly seen during the first infusion, usually in the first oneto two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms includedflushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throatirritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia,asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such asbronchospasm, hypotension) occurred in up to 12% of the cases.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonaryoedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions suchas angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardialinfarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokinerelease syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies.

The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is< 1% of patients by the eighth cycle of rituximab (containing) treatment.

Rituximab induces B-cell depletion in about 70-80% of patients, but was associated with decreasedserum immunoglobulins only in a minority of patients.

Localised candida infections as well as Herpes zoster were reported at a higher incidence in therituximab-containing arm of randomised studies. Severe infections were reported in about 4% ofpatients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade3 or 4 infections, were observed during rituximab maintenance treatment up to 2 years when comparedto observation. There was no cumulative toxicity in terms of infections reported over a 2-yeartreatment period. In addition, other serious viral infections either new, reactivated or exacerbated,some of which were fatal, have been reported with rituximab treatment. The majority of patients hadreceived rituximab in combination with chemotherapy or as part of a haematopoietic stem celltransplant. Examples of these serious viral infections are infections caused by the herpes viruses(Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocalleukoencephalopathy [PML]), enterovirus (meningoencephalitis) and hepatitis C virus (see section4.4.). Cases of fatal PML that occurred after disease progression and retreatment have also beenreported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of whichwere in patients receiving rituximab in combination with cytotoxic chemotherapy. In patients withrelapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primaryinfection) was 2% in R-FC vs. 0% FC. Progression of Kaposi’s sarcoma has been observed inrituximab-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in non-approvedindications and the majority of patients were HIV positive.

In clinical trials with rituximab monotherapy given for 4 weeks, haematological abnormalitiesoccurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropeniawas reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. Duringrituximab maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and neutropenia(10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to observation. Theincidence of thrombocytopenia was low (< 1%, grade 3/4) and was not different between treatmentarms. During the treatment course in studies with rituximab in combination with chemotherapy,grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), neutropenia (R-CVP24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated

CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported withhigher frequencies when compared to chemotherapy alone. However, the higher incidence ofneutropenia in patients treated with rituximab and chemotherapy was not associated with a higherincidence of infections and infestations compared to patients treated with chemotherapy alone. Studiesin previously untreated and relapsed/refractory CLL have established that in up to 25% of patientstreated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1 x 109/Lbetween Day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil countbelow 1 x 109/L later than 42 days after last dose in patients with no previous prolonged neutropeniaor who recovered prior to Day 42) following treatment with rituximab plus FC. There were nodifferences reported for the incidence of anaemia. Some cases of late neutropenia occurring more thanfour weeks after the last infusion of rituximab were reported. In the CLL first-line study, Binet stage Cpatients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% ofpatients in the R-FC group compared to 9% of patients in the FC group.

In studies of rituximab in patients with Waldenstrom’s macroglobulinaemia, transient increases inserum IgM levels have been observed following treatment initiation, which may be associated withhyperviscosity and related symptoms. The transient IgM increase usually returned to at least baselinelevel within 4 months.

Cardiovascular reactions during clinical trials with rituximab monotherapy were reported in 18.8% ofpatients with the most frequently reported events being hypotension and hypertension. Cases ofgrade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectorisduring infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiacdisorders was comparable between patients treated with rituximab and observation. Cardiac eventswere reported as serious adverse reactions (including atrial fibrillation, myocardial infarction, leftventricular failure, myocardial ischaemia) in 3% of patients treated with rituximab compared to < 1%on observation. In studies evaluating rituximab in combination with chemotherapy, the incidence ofgrade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardiaand atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the

CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a rituximabinfusion or were associated with predisposing conditions such as fever, infection, acute myocardialinfarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOPand CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heartfailure, myocardial disease and manifestations of coronary artery disease. In CLL, the overallincidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) andin the relapsed/refractory study (4% R-FC, 4% FC).

Cases of interstitial lung disease, some with fatal outcome have been reported.

During the treatment period (induction treatment phase comprising of R-CHOP for at most eightcycles), four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experiencedthromboembolic cerebrovascular accidents during the first treatment cycle. There was no differencebetween the treatment groups in the incidence of other thromboembolic events. In contrast, threepatients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during thefollow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low bothin the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC).

Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posteriorleukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visualdisturbance, headache, seizures and altered mental status, with or without associated hypertension. Adiagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognizedrisk factors for PRES/RPLS, including the patients’ underlying disease, hypertension,immunosuppressive therapy and/or chemotherapy.

Gastrointestinal perforation in some cases leading to death has been observed in patients receivingrituximab for treatment of NHL. In the majority of these cases, rituximab was administered withchemotherapy.

In the clinical trial evaluating rituximab maintenance treatment in relapsed/refractory follicularlymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after inductiontreatment in both the observation and the rituximab groups. In the observation group, the median IgGlevel subsequently increased to above the LLN, but remained constant in the rituximab group. Theproportion of patients with IgG levels below the LLN was about 60% in the rituximab groupthroughout the 2-year treatment period, while it decreased in the observation group (36% after2 years).

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observedin paediatric patients treated with rituximab, in some cases severe and requiring long-termimmunoglobulin substitution therapy. The consequences of long term B-cell depletion in paediatricpatients are unknown.

Toxic Epidermal Necrolysis (Lyell syndrome) and Stevens-Johnson syndrome, some with fataloutcome, have been reported very rarely.

Patient subpopulations - rituximab monotherapy

Elderly (65 years and above)

The incidence of adverse reactions of all grades and grade 3 /4 adverse reactions was similar in elderlypatients compared to younger patients (below 65 years).

There was a higher incidence of grade 3/4 adverse reactions in patients with bulky disease than inpatients without bulky disease (25.6% vs. 15.4%). The incidence of adverse reactions of any gradewas similar in these two groups.

The percentage of patients reporting adverse reactions upon re-treatment with further courses ofrituximab was similar to the percentage of patients reporting adverse reactions upon initial exposure(any grade and grade 3/4 adverse reactions).

Patient subpopulations - rituximab combination therapy

Elderly (65 years and above)

The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patientscompared to younger patients (below 65 years), with previously untreated or relapsed/refractory CLL.

A multicentre, open-label randomised study of Lymphome Malin B chemotherapy (LMB) with orwithout rituximab was conducted in paediatric patients (aged 6 months to less than 18 years old) withpreviously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL.

A total of 309 paediatric patients received rituximab and were included in the safety analysispopulation. Paediatric patients randomised to the LMB chemotherapy arm with rituximab, or enrolledin the single arm part of the study, were administered rituximab at a dose of 375 mg/m2 BSA andreceived a total of six intravenous infusions of rituximab (two during each of the two inductioncourses and one during each of the two consolidation courses of the LMB scheme).

The safety profile of rituximab in paediatric patients (aged 6 months to less than 18 years old) withpreviously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL was generally consistent intype, nature and severity with the known safety profile in adult NHL and CLL patients. Addition ofrituximab to chemotherapy did result in an increased risk of some events including infections(including sepsis) compared to chemotherapy only.

The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients fromclinical trials and from post-marketing surveillance.

The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) issummarised in the sections below. In clinical trials more than 3,100 patients received at least onetreatment course and were followed for periods ranging from 6 months to over 5 years; approximately2,400 patients received two or more courses of treatment with over 1,000 having received 5 or morecourses. The safety information collected during post marketing experience reflects the expectedadverse reaction profile as seen in clinical trials for rituximab (see section 4.4).

Patients received 2 x 1,000 mg of rituximab separated by an interval of two weeks; in addition tomethotrexate (10 - 25 mg/week). Rituximab infusions were administered after an intravenous infusionof 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days.

Adverse reactions are listed in Table 4. Frequencies are defined as very common (≥ 1/10), common(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare(< 1/10,000) and not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in the order of decreasing seriousness.

The adverse reactions identified only during post marketing surveillance, and for which a frequencycould not be estimated, are listed under “not known”, see footnotes.

The most frequent adverse reactions considered due to receipt of rituximab IRRs. The overallincidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequentinfusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during theinitial course. In addition to adverse reactions seen in RA clinical trials for rituximab, progressivemultifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like reaction have beenreported during post marketing experience.

Table 4 Summary of adverse reactions reported in clinical trials or during post-marketingsurveillance occurring in patients with rheumatoid arthritis receiving rituximab

MedDRA Not known

System organ Very common Common Uncommon Rare Very rareclass

Infections and Upper Bronchitis, PML, serious viralinfestations respiratory sinusitis, reactivatio infection1, 2,tract infection, gastroenteritis, n of enteroviralurinary tract tinea pedis hepatitis B meningoencinfections ephalitis2

Blood and Neutropenia3 Late Serumlymphatic neutropenia4 sickness-system disorders likereaction

Immune system 5Infusion- 5Infusion-disorders related related

General reactions reactionsdisorders and (hypertension, (generalisedadministration nausea, rash, oedema,site conditions pyrexia, bronchospasm,pruritus, wheezing,urticaria, throat laryngealirritation, hot oedema,flush, angioneurotichypotension, oedema,rhinitis, rigors, generalisedtachycardia, pruritus,fatigue, anaphylaxis,oropharyngeal anaphylactoidpain, oedema reaction)peripheral,erythema)

Metabolism and Hypercholestenutrition rolemiadisorders

Psychiatric Depression,disorders anxiety

Nervous system Headache Paraesthesia,disorders migraine,dizziness,sciatica

MedDRA Not known

System organ Very common Common Uncommon Rare Very rareclass

Cardiac Angina Atrialdisorders pectoris, flutteratrialfibrillation,heart failure,myocardialinfarction

Gastrointestinal Dyspepsia,disorders diarrhoea,gastro-oesophagealreflux, mouthulceration,upperabdominalpain

Skin and Alopecia Toxicsubcutaneous Epidermaltissue disorders Necrolysis(Lyell’ssyndrome), Stevens-

Johnsonsyndrome7

Musculoskeletal Arthralgia /disorders and musculoskeletconnective tissue al pain,disorders osteoarthritis,bursitis

Investigations Decreased IgM Decreased IgGlevels6 levels61 See also section infections below.2 Observed during post-marketing surveillance3 Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials.4 Frequency category derived from post-marketing data.5 Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRs may occuras a result of hypersensitivity and/or to the mechanism of action.6 Includes observations collected as part of routine laboratory monitoring.7 Includes fatal cases.

Multiple courses of treatment are associated with a similar adverse reaction profile to that observedfollowing first exposure. The rate of all adverse reactions following first rituximab exposure washighest during the first 6 months and declined thereafter. This is mostly accounted for by IRRs (mostfrequent during the first treatment course), RA exacerbation and infections, all of which were morefrequent in the first 6 months of treatment.

The most frequent adverse reactions following receipt of rituximab in clinical studies were IRRs (referto Table 4). Among the 3 189 patients treated with rituximab, 1 135 (36%) experienced at least one

IRR with 733/3 189 (23%) of patients experiencing an IRR following first infusion of the firstexposure to rituximab. The incidence of IRRs declined with subsequent infusions. In clinical trialsfewer than 1% (17/3 189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRsand no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRsleading to withdrawal decreased by course and were rare from course 3 onwards. Premedication withintravenous glucocorticoid significantly reduced the incidence and severity of IRRs (seesections 4.2 and 4.4). Severe IRRs with fatal outcome have been reported in the post-marketingsetting.

In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with rheumatoidarthritis, patients with moderate-to-severe active RA who did not experience a serious IRR during orwithin 24 hours of their first studied infusion were allowed to receive a 2-hour intravenous infusion ofrituximab. Patients with a history of a serious infusion reaction to a biologic therapy for RA wereexcluded from entry. The incidence, types and severity of IRRs were consistent with that observedhistorically. No serious IRRs were observed.

The overall rate of infection reported from clinical trials was approximately 94 per 100 patient years inrituximab treated patients. The infections were predominately mild to moderate and consisted mostlyof upper respiratory tract infections and urinary tract infections. The incidence of infections that wereserious or required intravenous antibiotics was approximately 4 per 100 patient years. The rate ofserious infections did not show any significant increase following multiple courses of rituximab.

Lower respiratory tract infections (including pneumonia) have been reported during clinical trials, at asimilar incidence in the rituximab arms compared to control arms.

In the post marketing setting, serious viral infections have been reported in RA patients treatedwith rituximab.

Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported followinguse of rituximab for the treatment of autoimmune diseases. This includes rheumatoid arthritis andoff-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and vasculitis.

In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxicchemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma).

Reactivation of hepatitis B infection has also been very rarely reported in RA patients receivingrituximab (see section 4.4).

Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the rituximab treatedpatients compared to 1.3 per 100 patient years in placebo treated patients. The proportions of patientsexperiencing cardiac reactions (all or serious) did not increase over multiple courses.

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posteriorleukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visualdisturbance, headache, seizures and altered mental status, with or without associated hypertension. Adiagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognisedrisk factors for PRES/RPLS, including the patients’ underlying disease, hypertension,immunosuppressive therapy and/or chemotherapy.

Events of neutropenia were observed with rituximab treatment, the majority of which were transientand mild or moderate in severity. Neutropenia can occur several months after the administration ofrituximab (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1 382) of rituximab treated patients and0.27% (2/731) of placebo patients developed severe neutropenia.

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reportedin the post-marketing setting, some of which were associated with fatal infections.

Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fataloutcome, have been reported very rarely.

Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RApatients treated with rituximab. There was no increased rate in overall infections or serious infectionsafter the development of low IgG or IgM (see section 4.4).

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observedin paediatric patients treated with rituximab, in some cases severe and requiring long-termimmunoglobulin substitution therapy. The consequences of long-term B-cell depletion in paediatricpatients are unknown.

Experience from granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)

The overall safety profile of rituximab in adult and paediatric GPA/MPA patients is based on datafrom patients from 3 clinical trials and from post-marketing surveillance.

In GPA/MPA Study 1, 99 adult patients were treated for induction of remission of GPA and MPAwith rituximab (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1).

The adverse reactions from GPA/MPA Study 1 listed in Table 5 with a frequency categorisation of'common' or 'very common' were all adverse events which occurred at an incidence of ≥ 5% in therituximab group and at a higher frequency than the comparator group.

The adverse reactions identified only during post-marketing surveillance, and for which a frequencycould not be estimated, are listed under “not known”, see footnotes.

Table 5 Adverse reactions occurring at 6 months in ≥ 5% of adult patients receivingrituximab in GPA/MPA Study 1 (Rituximab n=99 at a higher frequency than thecomparator group), or during post-marketing surveillance.

MedDRA

System organ class Very common Common Not known

Infections and urinary tract infection, serious viral infection1, 2,infestations bronchitis, enteroviralherpes zoster, meningoencephalitis1nasopharyngitis

Blood and lymphatic thrombocytopeniasystem disorders

Immune system cytokine releasedisorders syndrome

Metabolism and hyperkalaemianutrition disorders

Psychiatric disorders insomnia

Nervous system dizziness,disorders tremor

Vascular disorders hypertension flushing

MedDRA Very common Common Not known

System organ class

Respiratory, thoracic cough, nasal congestionand mediastinal dyspnoea,disorders epistaxis

Gastrointestinal diarrhoea dyspepsia,disorders constipation

Skin and subcutaneous acnetissue disorders

Musculoskeletal and muscle spasms, muscle weakness,connective tissue arthralgia, musculoskeletal pain,disorders back pain pain in extremities

General disorders and oedema peripheraladministration siteconditions

Investigations decreased haemoglobin1 Observed during post-marketing surveillance.2 See also section infections below.

In GPA/MPA Study 2, a total of 57 adult patients with severe, active GPA and MPA were treated withrituximab for the maintenance of remission (see section 5.1).

Table 6 Adverse reactions occurring in ≥ 5% of adult patients receiving rituximab in

GPA/MPA Study 2 (Rituximab n=57), at a higher frequency than the comparatorgroup , or during post-marketing surveillance.

MedDRA Very common Common Not known

System organ class

Infections and bronchitis rhinitis serious viral infection1, 2,infestations enteroviralmeningoencephalitis1

Respiratory, thoracic dyspnoeaand mediastinaldisorders

Gastrointestinal diarrhoeadisorders

General disorders and pyrexia,administration site influenza-like illness,conditions oedema peripheral

Injury, poisoning and infusion-relatedprocedural reactions3complications1 Observed during post-marketing surveillance.2 See also section infections below.3 Details on infusion related reactions are provided in the description of selected adverse reactions section.

The overall safety profile was consistent with the well-established safety profile for rituximab inapproved autoimmune indications, including GPA and MPA. Overall, 4% of patients in the rituximabarm experienced adverse events leading to discontinuation. Most adverse events in the rituximab armwere mild or moderate in intensity. No patients in the rituximab arm had fatal adverse events.

The most commonly reported events considered as adverse reactions were infusion-related reactionsand infections.

In a long-term observational safety study, 97 GPA and MPA patients received treatment withrituximab (mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician’s standardpractice and discretion. The overall safety profile was consistent with the well-established safetyprofile of rituximab in RA and GPA and MPA and no new adverse reactions were reported.

An open-label, single arm study was conducted in 25 paediatric patients with severe, active GPA or

MPA. The overall study period consisted of a 6-month remission induction phase with a minimum 18-month follow-up, up to 4.5 years overall. During the follow-up phase, Rituximab was given at thediscretion of the investigator (17 out of 25 patients received additional rituximab treatment).

Concomitant treatment with other immunosuppressive therapy was permitted (see section 5.1).

Adverse reactions were considered as adverse events that occurred at an incidence of ≥ 10%. Theseincluded: infections (17 patients [68%] in the remission induction phase; 23 patients [92%] in theoverall study period), IRRs (15 patients [60%] in the remission induction phase; 17 patients [68%] inthe overall study period), and nausea (4 patients [16%] in the remission induction phase; 5 patients[20%] in the overall study period).

During the overall study period, the safety profile of rituximab was consistent with that reportedduring the remission induction phase.

The safety profile of rituximab in paediatric GPA or MPA patients was consistent in type, nature andseverity with the known safety profile in adult patients in the approved autoimmune indications,including adult GPA or MPA.

In GPA/MPA Study 1 (adult induction of remission study), IRRs were defined as any adverse eventoccurring within 24 hours of an infusion and considered to be infusion-related by investigators in thesafety population. Of the 99 patients treated with rituximab, 12 (12%) experienced at least one IRR.

All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome,flushing, throat irritation, and tremor. Rituximab was given in combination with intravenousglucocorticoids which may reduce the incidence and severity of these events.

In GPA/MPA Study 2 (adult maintenance study), 7/57 (12%) patients in the rituximab armexperienced at least one infusion-related reaction. The incidence of IRR symptoms was highest duringor after the first infusion (9%) and decreased with subsequent infusions (< 4%). All IRR symptomswere mild or moderate and most of them were reported from the SOCs Respiratory, Thoracic and

Mediastinal Disorders and Skin and Subcutaneous Tissue disorders.

In the clinical trial in paediatric patients with GPA or MPA, the reported IRRs were predominantlyseen with the first infusion (8 patients [32%]), and then decreased over time with the number ofrituximab infusions (20% with the second infusion, 12% with the third infusion and 8% with thefourth infusion). The most common IRR symptoms reported during the remission induction phasewere: headache, rash, rhinorrhoea and pyrexia (8%, for each symptom). The observed symptoms of

IRRs were similar to those known in adult GPA or MPA patients treated with rituximab. The majorityof IRRs were Grade 1 and Grade 2, there were two non-serious Grade 3 IRRs, and no Grade 4 or 5

IRRs reported. One serious Grade 2 IRR (generalised oedema which resolved with treatment) wasreported in one patient (see section 4.4).

In GPA/MPA Study 1, the overall rate of infection was approximately 237 per 100 patient years(95% CI 197 - 285) at the 6-month primary endpoint. Infections were predominately mild to moderateand consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections.

The rate of serious infections was approximately 25 per 100 patient years. The most frequentlyreported serious infection in the rituximab group was pneumonia at a frequency of 4%.

In GPA/MPA Study 2, 30/57 (53%) patients in the rituximab arm experienced infections. Theincidence of all grade infections was similar between the arms. Infections were predominately mild tomoderate. The most common infections in the rituximab arm included upper respiratory tractinfections, gastroenteritis, urinary tract infections and herpes zoster. The incidence of seriousinfections was similar in both arms (approximately 12%). The most commonly reported seriousinfection in the rituximab group was mild or moderate bronchitis.

In the clinical trial in paediatric patients with severe, active GPA and MPA, 91% of reported infectionswere non-serious and 90% were mild to moderate.

The most common infections in the overall phase were: upper respiratory tract infections (URTIs)(48%), influenza (24%), conjunctivitis (20%), nasopharyngitis (20%), lower respiratory tractinfections (16%), sinusitis (16%), viral URTIs (16%), ear infection (12%), gastroenteritis (12%),pharyngitis (12%), urinary tract infection (12%). Serious infections were reported in 7 patients (28%),and included: influenza (2 patients [8%]) and lower respiratory tract infection (2 patients [8%]) as themost frequently reported events.

In the post marketing setting, serious viral infections have been reported in GPA/MPA patientstreated with rituximab.

In GPA/MPA Study 1, the incidence of malignancy in rituximab treated patients in the GPA and MPAclinical study was 2.00 per 100 patient years at the study common closing date (when the final patienthad completed the follow-up period). On the basis of standardised incidence ratios, the incidence ofmalignancies appears to be similar to that previously reported in patients with ANCA-associatedvasculitis.

In the paediatric clinical trial, no malignancies were reported with a follow-up period of up to54 months.

In GPA/MPA Study 1, cardiac events occurred at a rate of approximately 273 per 100 patient years(95% CI 149 - 470) at the 6-month primary endpoint. The rate of serious cardiac events was2.1 per 100 patient years (95% CI 3 - 15). The most frequently reported events were tachycardia (4%)and atrial fibrillation (3%) (see section 4.4).

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posteriorleukoencephalopathy syndrome (RPLS) have been reported in autoimmune conditions. Signs andsymptoms included visual disturbance, headache, seizures and altered mental status, with or withoutassociated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. Thereported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease,hypertension, immunosuppressive therapy and/or chemotherapy.'

A small number of cases of hepatitis-B reactivation, some with fatal outcome, have been reported in

GPA and MPA patients receiving rituximab in the post-marketing setting.

Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed inadult and paediatric GPA and MPA patients treated with rituximab.

In GPA/MPA Study 1, at 6 months, in the rituximab group, 27%, 58% and 51% of patients withnormal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to25%, 50% and 46% in the cyclophosphamide group. The rate of overall infections and seriousinfections was not increased after the development of low IgA, IgG or IgM.

In GPA/MPA Study 2, no clinically meaningful differences between the two treatment arms ordecreases in total immunoglobulin, IgG, IgM or IgA levels were observed throughout the trial.

In the paediatric clinical trial, during the overall study period, 3/25 (12%) patients reported an event ofhypogammaglobulinaemia, 18 patients (72%) had prolonged (defined as Ig levels below lower limit ofnormal for at least 4 months) low IgG levels (of whom 15 patients also had prolonged low IgM).

Three patients received treatment with intravenous immunoglobulin (IV-IG). Based on limited data,no firm conclusions can be drawn regarding whether prolonged low IgG and IgM led to an increasedrisk of serious infection in these patients. The consequences of long-term B-cell depletion in paediatricpatients are unknown.

In GPA/MPA Study 1, 24% of patients in the rituximab group (single course) and 23% of patients inthe cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was notassociated with an observed increase in serious infection in rituximab-treated patients.

In GPA/MPA Study 2, the incidence of all-grade neutropenia was 0% for rituximab-treated patients vs5% for azathioprine treated patients.

Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fataloutcome, have been reported very rarely.

The overall safety profile of rituximab in pemphigus vulgaris is based on data from patients from 2clinical trials and from post-marketing surveillance.

The safety profile of rituximab in combination with short-term, low-dose glucocorticoids in thetreatment of patients with PV was studied in a Phase 3, randomised, controlled, multicentre, open-label study in pemphigus patients that included 38 PV patients randomised to the rituximab group (PV

Study I). Patients randomised to the rituximab group received an initial 1000 mg intravenously on

Study Day 1 and a second 1000 mg intravenously on Study Day 15. Maintenance doses of 500 mgintravenously were administered at months 12 and 18. Patients could receive 1000 mg intravenously atthe time of relapse (see section 5.1).

In PV Study 2, a randomised, double-blind, double-dummy, active-comparator, multicentre studyevaluating the efficacy and safety of rituximab compared with mycophenolate mofetil (MMF) inpatients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatmentwith rituximab (initial 1000 mg intravenously on Study Day 1 and a second 1000 mg intravenouslyon Study Day 15 repeated at Weeks 24 and 26) for up to 52 weeks (see section 5.1).

The safety profile of rituximab in PV was consistent with the established safety profile in otherapproved autoimmune indications.

Tabulated list of adverse reactions for PV Studies 1 and 2, or during post-marketing surveillance

The adverse reactions from PV Studies 1 and 2 with a frequency categorisation of 'common' or 'verycommon' are presented in Table 7. In PV Study 1, adverse reactions were defined as adverse eventswhich occurred at a rate of  5% among rituximab-treated PV patients, with a  2% absolutedifference in incidence between the rituximab-treated group and the standard-dose prednisone groupup to Month 24. No patients were withdrawn due to adverse reactions in Study 1. In PV Study 2,adverse reactions were defined as adverse events occurring in ≥ 5% of patients in the rituximab armand assessed as related.

The adverse reactions identified only during post-marketing surveillance, and for which a frequencycould not be estimated, are listed under “not known”, see footnotes.

Table 7 Adverse reactions in rituximab-treated PV patients PV Study 1 (up to Month 24)and PV Study 2 (up to Week 52), or during post-marketing surveillance

MedDRA Not known

System Organ Class Very common Common

Infections and infestations Upper respiratory Herpes virus infection Serious viraltract infection Herpes zoster infection1, 2

Oral herpes Enteroviral

Conjunctivitis meningoencephalitis1

Nasopharyngitis

Oral candidiasis

Neoplasms benign, Skin papillomamalignant and unspecified(incl. cysts and polyps)

Psychiatric disorders Persistent Major depressiondepressive Irritabilitydisorder

Nervous system disorders Headache Dizziness

Cardiac disorders Tachycardia

Gastrointestinal disorders Abdominal pain upper

Skin and subcutaneous Alopecia Pruritustissue disorders Urticaria

Skin disorder

Musculoskeletal and Musculoskeletal painconnective tissue disorders Arthralgia

Back pain

General disorders and Fatigueadministration site Astheniaconditions Pyrexia

Injury, poisoning and Infusion-relatedprocedural complications reactions31 Observed during post-marketing surveillance.2 See also section infections below.3 Infusion-related reactions for PV Study 1 included symptoms collected on the next scheduled visit after each infusion, andadverse reactions occurring on the day of or one day after the infusion. The most common infusion-related reactionsymptoms/Preferred Terms for PV Study 1 included headaches, chills, high blood pressure, nausea, asthenia and pain.

The most common infusion-related reaction symptoms/Preferred Terms for PV Study 2 were dyspnoea, erythema,hyperhidrosis, flushing/hot flush, hypotension/low blood pressure and rash/rash pruritic.

In PV Study 1, infusion-related reactions were common (58%). Nearly all infusion-related reactionswere mild to moderate. The proportion of patients experiencing an infusion- related reaction was 29%(11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second,third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-related reactions. Symptoms of infusion-related reactions were similar in type and severity to thoseseen in RA and GPA/MPA patients.

In PV Study 2, IRRs occurred primarily at the first infusion and the frequency of IRRs decreased withsubsequent infusions: 17.9%, 4.5%, 3% and 3% of patients experienced IRRs at the first, second, third,and fourth infusions, respectively. In 11/15 patients who experienced at least one IRR, the IRRs were

Grade 1 or 2. In 4/15 patients, Grade ≥ 3 IRRs were reported and led to discontinuation of rituximabtreatment; three of the four patients experienced serious (life-threatening) IRRs. Serious IRRsoccurred at the first (2 patients) or second (1 patient) infusion and resolved with symptomatictreatment.

In PV Study 1, 14 patients (37%) in the rituximab group experienced treatment-related infectionscompared to 15 patients (42%) in the standard-dose prednisone group. The most common infections inthe rituximab group were herpes simplex and zoster infections, bronchitis, urinary tract infection,fungal infection and conjunctivitis. Three patients (8%) in the rituximab group experienced a total of 5serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis,lung infection, Staphylococcal sepsis) and one patient (3%) in the standard-dose prednisone groupexperienced a serious infection (Pneumocystis jirovecii pneumonia).

In PV Study 2, 42 patients (62.7%) in the rituximab arm experienced infections. The most commoninfections in the rituximab group were upper respiratory tract infection, nasopharyngitis, oralcandidiasis and urinary tract infection. Six patients (9%) in the rituximab arm experienced seriousinfections.

In the post marketing setting, serious viral infections have been reported in PV patients treated withrituximab.

In PV Study 2, in the rituximab arm, transient decreases in lymphocyte count, driven by decreases inthe peripheral T-cell populations, as well as a transient decrease in phosphorus level were verycommonly observed post-infusion. These were considered to be induced by IV methylprednisolonepremedication infusion.

In PV Study 2, low IgG levels were commonly observed and low IgM levels were very commonlyobserved; however, there was no evidence of an increased risk of serious infections after thedevelopment of low IgG or IgM.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Limited experience with doses higher than the approved dose of intravenous rituximab formulation isavailable from clinical trials in humans. The highest intravenous dose of rituximab tested in humans todate is 5,000 mg (2,250 mg/m²), tested in a dose escalation study in patients with CLL. No additionalsafety signals were identified.

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

In the post-marketing setting five cases of rituximab overdose have been reported. Three cases had noreported adverse event. The two adverse events that were reported were flu-like symptoms, with adose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drugconjugates, ATC code: L01FA01

Rixathon is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency https://www.ema.europa.eu.

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylatedphosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95% of all

B-cell non-Hodgkin’s lymphomas.

CD20 is found on both normal and malignant B-cells, but not on haematopoietic stem cells, pro B-cells, normal plasma cells or other normal tissue. This antigen does not internalise upon antibodybinding and is not shed from the cell surface. CD20 does not circulate in the plasma as a free antigenand, thus, does not compete for antibody binding.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain canrecruit immune effector functions to mediate B6-cell lysis. Possible mechanisms of effector-mediatedcell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, andantibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on thesurface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on Blymphocytes has also been demonstrated to induce cell death via apoptosis.

Peripheral B-cell counts declined below normal following completion of the first dose of rituximab. Inpatients treated for haematological malignancies, B-cell recovery began within 6 months of treatmentand generally returned to normal levels within 12 months after completion of therapy, although insome patients this may take longer (up to a median recovery time of 23 months post-inductiontherapy). In rheumatoid arthritis patients, immediate depletion of B-cells in the peripheral blood wasobserved following two infusions of 1,000 mg rituximab separated by a 14-day interval. Peripheralblood B-cell counts begin to increase from Week 24 and evidence for repopulation is observed in themajority of patients by Week 40, whether rituximab was administered as monotherapy or incombination with methotrexate. A small proportion of patients had prolonged peripheral B-celldepletion lasting 2 years or more after their last dose of rituximab. In patients with GPA or MPA, thenumber of peripheral blood B-cells decreased to < 10 cells/μL after two weekly infusions of rituximab375 mg/m2, and remained at that level in most patients up to the 6 month time point. The majority ofpatients (81%) showed signs of B-cell return, with counts > 10 cells/μL by Month 12, increasing to87% of patients by Month 18.

Clinical efficacy and safety in non-Hodgkin’s lymphoma (NHL) and in chronic lymphocyticleukaemia (CLL)

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B-cell NHLreceived 375 mg/m2 of rituximab as an intravenous infusion once weekly for four weeks. The overallresponse rate (ORR) in the intent-to-treat (ITT) population was 48% (CI95% 41%-56%) with a 6%complete response (CR) and a 42% partial response (PR) rate. The projected median time toprogression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR washigher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58%vs. 12%), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53% vs.38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined asduration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated withautologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT. Neitherage, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high

LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) onresponse to rituximab. A statistically significant correlation was noted between response rates andbone marrow involvement. 40% of patients with bone marrow involvement responded compared to59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by astepwise logistic regression analysis in which the following factors were identified as prognosticfactors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulkydisease.

In a multi-centre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular

B-cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for eight doses. The

ORR was 57% (95% Confidence interval (CI); 41% - 73%; CR 14%, PR 43%) with a projectedmedian TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).

In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (singlelesion ≥ 10 cm in diameter), low grade or follicular B-cell NHL received 375 mg/m2 of rituximab asintravenous infusion weekly for four doses. The ORR was 36% (CI95% 21% - 51%; CR 3%, PR 33%)with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

In a multi-centre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular

B-cell NHL, who had achieved an objective clinical response to a prior course of rituximab, werere-treated with 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. Three of thepatients had received two courses of rituximab before enrolment and thus were given a third course inthe study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORRwas 38% (CI95% 26% - 51%; CR 10%, PR 28%) with a projected median TTP for responding patientsof 17.8 months (range 5.4-26.6). This compares favourably with the TTP achieved after the priorcourse of rituximab (12.4 months).

In an open-label randomised trial, a total of 322 previously untreated patients with follicularlymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2,vincristine 1.4 mg/m2 up to a maximum of 2 mg on Day 1, and prednisolone 40 mg/m2/day on days 1 -5) every 3 weeks for 8 cycles or rituximab 375 mg/m2 in combination with CVP (R-CVP). Rituximabwas administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP,159 CVP) received therapy and were analysed for efficacy. The median follow-up of patients was53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatmentfailure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumourresponse (CR, CRu, PR) was significantly higher (p < 0.0001 Chi-Square test) in the R-CVP group(80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time todisease progression or death compared to CVP, 33.6 months and 14.7 months, respectively(p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group andwas 13.5 months in the CVP group (p < 0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significantclinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were 80.9%for patients in the R-CVP group compared to 71.1% for patients in the CVP group.

Results from three other randomised trials using rituximab in combination with chemotherapy regimenother than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant improvementsin response rates, time-dependent parameters as well as in overall survival. Key results from all fourstudies are summarised in Table 8.

Table 8 Summary of key results from four phase III randomised studies evaluating thebenefit of rituximab with different chemotherapy regimens in follicular lymphoma

Study Treatment, N Median ORR, % CR, % Median OS rates, %

FU, TTF/PFS/ EFS,months months

Median TTP: 53-months

M39021 CVP, 159 53 57 10 14.7 71.1

R-CVP, 162 81 41 33.6 80.9p < 0.0001 p=0.029

Median TTF: 2.6 18-months

GLSG’00 CHOP, 205 90 17 years 90

R-CHOP, 223 18 96 20 Not reached 95p < 0.001 p=0.016

MCP, 96 75 25 Median PFS: 28.8 48-months

OSHO-39 47 Not reached 74

R-MCP, 105 92 50 p < 0.0001 87p=0.0096

CHVP-IFN, Median EFS: 36 42-months

FL2000 183 85 49

R-CHVP- 42 94 76 Not reached 84

IFN, 175 p < 0.0001 91p=0.029

EFS - Event Free Survival

TTP - Time to progression or death

PFS - Progression-Free Survival

TTF - Time to Treatment Failure

OS rates - survival rates at the time of the analyses

In a prospective, open label, international, multi-centre, phase III trial 1 193 patients with previouslyuntreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP(n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1 078 patients respondedto induction therapy, of which 1 018 were randomised to rituximab maintenance therapy (n=505) orobservation (n=513). The two treatment groups were well balanced with regards to baselinecharacteristics and disease status. Rituximab maintenance treatment consisted of a single infusion ofrituximab at 375 mg/m2 body surface area given every 2 months until disease progression or for amaximum period of two years.

The pre-specified primary analysis was conducted at a median observation time of 25 months fromrandomisation, maintenance therapy with rituximab resulted in a clinically relevant and statisticallysignificant improvement in the primary endpoint of investigator assessed progression-free survival(PFS) as compared to observation in patients with previously untreated follicular lymphoma (Table 9).

Significant benefit from maintenance treatment with rituximab was also seen for the secondaryendpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to nextchemotherapy (TNCT) and overall response rate (ORR) in the primary analysis (Table 9).

Data from extended follow up of patients in the study (median follow-up 9 years) confirmed the long-term benefit of rituximab maintenance therapy in terms of PFS, EFS, TNLT, and TNCT (Table 9).

Table 9 Overview of efficacy results for rituximab maintenance vs. observation at theprotocol-defined primary analysis and after 9 years median follow-up (finalanalysis)

Primary analysis Final analysis(median FU: 25 (median FU:9.0 years)months)

Observation Rituximab Observation Rituximab

N=513 N=505 N=513 N=505

Primary efficacy

Progression-free survival NR NR 4.06 years 10.49 years(median) < 0.0001 < 0.0001log-rank p value 0.50 (0.39, 0.64) 0.61 (0.52, 0.73)hazard ratio (95% CI) 50% 39%risk reduction

Secondary efficacy

Overall survival NR NR NR NR(median) 0.7246 0.7948log-rank p value 0.89 (0.45, 1.74) 1.04 (0.77, 1.40)hazard ratio (95% CI) 11% -6%risk reduction

Event-free survival (median) 38 months NR 4.04 years 9.25 yearslog-rank p value < 0.0001 < 0.0001hazard ratio (95% CI) 0.54 (0.43, 0.69) 0.64 (0.54, 0.76)risk reduction 46% 36%

TNLT (median) NR NR 6.11 years NRlog-rank p value 0.0003 < 0.0001<hazard ratio (95% CI) 0.61 (0.46, 0.80) 0.66 (0.55, 0.78)risk reduction 39% 34%

TNCT (median) NR NR 9.32 years NRlog-rank p value 0.0011 0.0004hazard ratio (95% CI) 0.60 (0.44, 0.82) 0.71 (0.59, 0.86)risk reduction 40% 39%

Overall response rate* 55% 74% 61% 79%chi-squared test p value < 0.0001 < 0.0001odds ratio (95% CI) 2.33 (1.73, 3.15) 2.43 (1.84, 3.22)

Complete response (CR/CRu) rate* 48% 67% 53% 72%chi-squared test p value < 0.0001 < 0.0001odds ratio (95% CI) 2.21 (1.65, 2.94) 2.34 (1.80, 3.03)

* at end of maintenance/observation; final analysis results based on median follow-up of 73 months.

FU: follow-up; NR: not reached at time of clinical cut off, TNCT: time to next chemotherapy treatment; TNLT:time to next anti lymphoma treatment.

Rituximab maintenance treatment provided consistent benefit in all predefined subgroups tested:gender (male, female), age (< 60 years, >= 60 years), FLIPI score (<=1, 2 or >= 3), induction therapy(R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment (CR,

CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less pronouncedeffect in elderly patients (> 70 years of age), however sample sizes were small.

In a prospective, open label, international, multi-centre, phase III trial, 465 patients withrelapsed/refractory follicular lymphoma were randomised in a first step to induction therapy witheither CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or rituximab plus

CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard to baselinecharacteristics and disease status. A total of 334 patients achieving a complete or partial remissionfollowing induction therapy were randomised in a second step to rituximab maintenance therapy(n=167) or observation (n=167). Rituximab maintenance treatment consisted of a single infusion ofrituximab at 375 mg/m2 body surface area given every 3 months until disease progression or for amaximum period of two years.

The final efficacy analysis included all patients randomised to both parts of the study. After a medianobservation time of 31 months for patients randomised to the induction phase, R-CHOP significantlyimproved the outcome of patients with relapsed/refractory follicular lymphoma when compared to

CHOP (see Table 10).

Table 10 Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 monthsmedian observation time)

CHOP R-CHOP p-value Risk reduction1)

Primary efficacy

ORR2) 74% 87% 0.0003 NA

CR2) 16% 29% 0.0005 NA

PR2) 58% 58% 0.9449 NA1) Estimates were calculated by hazard ratios2) Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was thetrend test of CR versus PR versus non-response (p < 0.0001)

Abbreviations: NA, not available; ORR: overall response rate; CR: complete response; PR: partial response

For patients randomised to the maintenance phase of the trial, the median observation time was28 months from maintenance randomisation. Maintenance treatment with rituximab led to a clinicallyrelevant and statistically significant improvement in the primary endpoint, PFS, (time frommaintenance randomisation to relapse, disease progression or death) when compared to observationalone (p < 0.0001 log-rank test). The median PFS was 42.2 months in the rituximab maintenance armcompared to 14.3 months in the observation arm. Using a cox regression analysis, the risk ofexperiencing progressive disease or death was reduced by 61% with rituximab maintenance treatmentwhen compared to observation (95% CI; 45% - 72%). Kaplan-Meier estimated progression- free ratesat 12 months were 78% in the rituximab maintenance group vs. 57% in the observation group. Ananalysis of overall survival confirmed the significant benefit of rituximab maintenance overobservation (p=0.0039 log-rank test). Rituximab maintenance treatment reduced the risk of death by56% (95% CI; 22% - 75%).

Table 11 Maintenance phase: overview of efficacy results rituximab vs. observation(28 months median observation time)

Efficacy parameter Kaplan-Meier estimate of Riskmedian time to event (months) reduction

Observation Rituximab Log-rank(N=167) (N=167) p value

Progression-free survival 14.3 42.2 < 0.0001 61%(PFS)

Overall survival NR NR 0.0039 56%

Time to new lymphoma 20.1 38.8 < 0.0001 50%treatment

Disease-free survivala 16.5 53.7 0.0003 67%

Efficacy parameter Kaplan-Meier estimate of Riskmedian time to event (months) reduction

Observation Rituximab Log-rank(N=167) (N=167) p value

PFS

CHOP 11.6 37.5 < 0.0001 71%

R-CHOP 22.1 51.9 0.0071 46%

CR 14.3 52.8 0.0008 64%

PR 14.3 37.8 < 0.0001 54%

OS

CHOP NR NR 0.0348 55%

R-CHOP NR NR 0.0482 56%

NR: not reached; a: only applicable to patients achieving a CR

The benefit of rituximab maintenance treatment was confirmed in all subgroups analysed, regardlessof induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR)(Table 11). Rituximab maintenance treatment significantly prolonged median PFS in patientsresponding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p < 0.0001) as wellas in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071).

Although subgroups were small, rituximab maintenance treatment provided a significant benefit interms of overall survival for both patients responding to CHOP and patients responding to R-CHOP,although longer follow-up is required to confirm this observation.

Adult diffuse large B-cell non-Hodgkin’s lymphoma

In a randomised, open-label trial, a total of 399 previously untreated elderly patients(age 60 to 80 years) with diffuse large B-cell lymphoma received standard CHOP chemotherapy(cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of2 mg on Day 1, and prednisolone 40 mg/m2/day on Days 1-5) every 3 weeks for eight cycles, orrituximab 375 mg/m2 plus CHOP (R-CHOP). Rituximab was administered on the first day of thetreatment cycle.

The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had amedian follow-up duration of approximately 31 months. The two treatment groups were well balancedin baseline disease characteristics and disease status. The final analysis confirmed that R-CHOPtreatment was associated with a clinically relevant and statistically significant improvement in theduration of event-free survival (the primary efficacy parameter; where events were death, relapse orprogression of lymphoma, or institution of a new anti-lymphoma treatment) (p=0.0001). Kaplan Meierestimates of the median duration of event-free survival were 35 months in the R-CHOP arm comparedto 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months, estimates foroverall survival were 68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequentanalysis of the duration of overall survival, carried out with a median follow-up duration of 60 months,confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), representing a risk reduction of32%.

The analysis of all secondary parameters (response rates, progression-free survival, disease-freesurvival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. Thecomplete response rate after cycle 8 was 76.2% in the R-CHOP group and 62.4% in the CHOP group(p=0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by 51%. In allpatients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2 microglobulin, LDH,albumin, B symptoms, bulky disease, extranodal sites, bone marrow involvement), the risk ratios forevent-free survival and overall survival (R-CHOP compared with CHOP) were less than 0.83 and 0.95respectively. R-CHOP was associated with improvements in outcome for both high- and low-riskpatients according to age adjusted IPI.

Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of356 patients evaluated for anti-drug antibody (ADA), 1.1% (4 patients) were positive.

In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients withrelapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2,cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or rituximab in combination with

FC (R-FC). Rituximab was administered at a dose of 375 mg/m2 during the first cycle one day prior tochemotherapy and at a dose of 500 mg/m2 on Day 1 of each subsequent treatment cycle. Patients wereexcluded from the study in relapsed/refractory CLL if they had previously been treated withmonoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission forat least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC,407 FC) for the first-line study (Table 12a and Table 12b) and 552 patients (276 R-FC, 276 FC) for therelapsed/refractory study (Table 13) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 monthsin the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overallsurvival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p=0.0319,log-rank test) (Table 12a). The benefit in terms of PFS was consistently observed in most patientsubgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 12b).

Table 12a First-line treatment of CLL

Overview of efficacy results for rituximab plus FC vs. FC alone - 48.1 monthsmedian observation time

Efficacy parameter Kaplan-Meier estimate of Riskmedian time to event (months) reduction

FC R-FC Log-rank(N=409) (N=408) p value

Progression-free survival (PFS) 32.8 55.3 < 0.0001 45%

Overall survival NR NR 0.0319 27%

Event free survival 31.3 51.8 < 0.0001 44%

Response rate (CR, nPR, or PR) 72.6% 85.8% < 0.0001 n.a.

CR rates 16.9% 36.0% < 0.0001 n.a.

Duration of response* 36.2 57.3 < 0.0001 44%

Disease free survival (DFS)** 48.9 60.3 0.0520 31%

Time to new treatment 47.2 69.7 < 0.0001 42%

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; n.a.: not applicable

*: only applicable to patients achieving a CR, nPR, PR

**: only applicable to patients achieving a CR

Table 12b First-line treatment of CLL

Hazard ratios of progression-free survival according to Binet stage (ITT) -48.1 months median observation time

Progression-free survival (PFS) Number of Hazard ratio p-valuepatients (95% CI) (Wald test,not adjusted)

FC R-FC

Binet stage A 22 18 0.39 (0.15; 0.98) 0.0442

Binet stage B 259 263 0.52 (0.41; 0.66) < 0.0001

Binet stage C 126 126 0.68 (0.49; 0.95) 0.0224

CI: Confidence Interval

In the relapsed/refractory study, the median progression-free survival (primary endpoint) was30.6 months in the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). Thebenefit in terms of PFS was observed in almost all patient subgroups analysed according to diseaserisk at baseline. A slight but not significant improvement in overall survival was reported in the R-FCcompared to the FC arm.

Table 13 Treatment of relapsed/refractory CLL - overview of efficacy results for rituximabplus FC vs. FC alone (25.3 months median observation time)

Efficacy parameter Kaplan-Meier estimate of Riskmedian time to event (months) reduction

FC R-FC Log-rank(N=276) (N=276) p value

Progression-free survival (PFS) 20.6 30.6 0.0002 35%

Overall survival 51.9 NR 0.2874 17%

Event free survival 19.3 28.7 0.0002 36%

Response rate (CR, nPR, or PR) 58.0% 69.9% 0.0034 n.a.

CR rates 13.0% 24.3% 0.0007 n.a.

Duration of response * 27.6 39.6 0.0252 31%

Disease free survival (DFS)** 42.2 39.6 0.8842 -6%

Time to new CLL treatment 34.2 NR 0.0024 35%

Response rate and CR rates analysed using Chi-squared Test.

*: only applicable to patients achieving a CR, nPR, PR; NR: not reached; n.a. not applicable

**: only applicable to patients achieving a CR;

Results from other supportive studies using rituximab in combination with other chemotherapyregimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment ofpreviously untreated and/or relapsed/refractory CLL patients have also demonstrated high overallresponse rates with benefit in terms of PFS rates, albeit with modestly higher toxicity (especiallymyelotoxicity). These studies support the use of rituximab with any chemotherapy.

Data in approximately 180 patients pre-treated with rituximab have demonstrated clinical benefit(including CR) and are supportive for rituximab re-treatment.

A multicentre, open-label, randomised study of Lymphome Malin B (LMB) chemotherapy(corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin,etoposide and triple drug [methotrexate/cytarabine/ corticosteroid] intrathecal therapy) alone or incombination with rituximab was conducted in paediatric patients with previously untreated advancedstage CD20 positive DLBCL/BL/BAL/BLL. Advanced stage is defined as Stage III with elevated

LDH level (“B-high”), (LDH > twice the institutional upper limit of the adult normal values [> Nx2])or any stage IV or BAL. Patients were randomised to receive either LMB chemotherapy or sixintravenous infusions of rituximab at a dose of 375 mg/m2 BSA in combination with LMBchemotherapy (two during each of the two induction courses and one during each of the twoconsolidation courses) as per the LMB scheme. A total of 328 randomised patients were included inthe efficacy analyses, of which one patient under 3 years of age received rituximab in combinationwith LMB chemotherapy.

The two treatment arms, LMB (LMB chemotherapy) and R-LMB (LMB chemotherapy withrituximab), were well balanced with regards to baseline characteristics. Patients had a median age of 7and 8 years in the LMB arm and R-LMB arm, respectively. Approximately half of patients were in

Group B (50.6% in the LMB arm and 49.4% in the R-LMB arm), 39.6% in Group C1 in both arms,and 9.8% and 11.0% were in Group C3 in the LMB and R-LMB arms, respectively. Based on Murphystaging, most patients were either BL stage III (45.7% in the LMB arm and 43.3% in the R-LMB arm)or BAL, CNS negative (21.3% in the LMB arm and 24.4% in the R-LMB arm). Less than half of thepatients (45.1% in both arms) had bone marrow involvement, and most patients (72.6% in the LMBarm and 73.2% in the R-LMB arm) had no CNS involvement. The primary efficacy endpoint was

EFS, where an event was defined as occurrence of progressive disease, relapse, second malignancy,death from any cause, or non-response as evidenced by detection of viable cells in residue after thesecond CYVE course, whichever occurs first. The secondary efficacy endpoints were OS and CR(complete remission).

At the pre-specified interim analysis with approximately 1 year of median follow-up, clinicallyrelevant improvement in the primary endpoint of EFS was observed, with 1-year rate estimates of94.2% (95% CI, 88.5% - 97.2%) in the R-LMB arm vs. 81.5% (95% CI, 73.0% - 87.8%) in the LMBarm, and adjusted Cox HR 0.33 (95% CI, 0.14 - 0.79). Upon IDMC (independent data monitoringcommittee) recommendation based on this result, the randomisation was halted and patients in the

LMB arm were allowed to cross over to receive rituximab.

Primary efficacy analyses were performed in 328 randomised patients with a median follow-up of3.1 years. The results are described in Table 14.

Table 14 Overview of primary efficacy results (ITT population)

Analysis LMB (N = 164) R-LMB (N = 164)

EFS 28 events 10 events

One-sided log-rank test p-value 0.0006

Adjusted Cox HR 0.32 (90% CI: 0.17, 0.58)3-year EFS rates 82.3% 93.9%(95% CI: 75.7%, 87.5%) (95% CI: 89.1%, 96.7%)

OS 20 deaths 8 deaths

One-sided log-rank test p-value 0.0061

Adjusted Cox model HR 0.36 (95% CI: 0.16; 0.81)3-year OS rates 87.3% 95.1%(95% CI: 81.2%, 91.6%) (95% CI: 90.5%, 97.5%)

CR rate 93.6% (95% CI: 88.2%; 97.0%) 94.0% (95% CI: 88.8%, 97.2%)

The primary efficacy analysis showed an EFS benefit of rituximab addition to LMB chemotherapyover LMB chemotherapy alone, with an EFS HR 0.32 (90% CI 0.17 - 0.58) from a Cox regressionanalysis adjusting for national group, histology, and therapeutic group. While no major differences innumbers of patients achieving CR was observed between the two treatment groups, the benefit ofrituximab addition to LMB chemotherapy was also shown in the secondary endpoint of OS, with the

OS HR of 0.36 (95% CI, 0.16 - 0.81).

The European Medicines Agency has waived the obligation to submit the results of studies withrituximab in all subsets of the paediatric population with follicular lymphoma and CLL, and in thepaediatric population from birth to < 6 months of age in CD20 positive diffuse large B-cell lymphoma.

See section 4.2 for information on paediatric use.

Clinical efficacy and safety in rheumatoid arthritis

The efficacy and safety of rituximab in alleviating the symptoms and signs of rheumatoid arthritis inpatients with an inadequate response to TNF-inhibitors was demonstrated in a pivotal randomised,controlled, double-blind, multicentre trial (Trial 1).

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one ormore TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according tothe criteria of the American College of Rheumatology (ACR). Rituximab was administered as twointravenous infusions separated by an interval of 15 days. Patients received 2 x 1,000 mg intravenousinfusions of rituximab or placebo in combination with MTX. All patients received concomitant 60 mgoral prednisone on days 2-7 and 30 mg on days 8-14 following the first infusion. The primary endpointwas the proportion of patients who achieved an ACR20 response at Week 24. Patients were followedbeyond Week 24 for long term endpoints, including radiographic assessment at 56 weeks and at104 weeks. During this time, 81% of patients, from the original placebo group received rituximabbetween weeks 24 and 56, under an open label extension study protocol.

Trials of rituximab in patients with early arthritis (patients without prior methotrexate treatment andpatients with an inadequate response to methotrexate, but not yet treated with TNF-alpha inhibitors)have met their primary endpoints. Rituximab is not indicated for these patients, since the safety dataabout long-term rituximab treatment are insufficient, in particular concerning the risk of developmentof malignancies and PML.

Rituximab in combination with methotrexate significantly increased the proportion of patientsachieving at least a 20% improvement in ACR score compared with patients treated with methotrexatealone (Table 15). Across all development studies the treatment benefit was similar in patientsindependent of age, gender, body surface area, race, number of prior treatments or disease status.

Clinically and statistically significant improvement was also noted on all individual components of the

ACR response (tender and swollen joint counts, patient and physician global assessment, disabilityindex scores (HAQ), pain assessment and C-Reactive Proteins (mg/dL).

Table 15 Clinical response outcomes at primary endpoint in Trial 1 (ITT population)

Outcome† Placebo+MTX Rituximab+MTX(2 x 1,000 mg)

Trial 1 N=201 N=298

ACR20 36 (18%) 153 (51%)***

ACR50 11 (5%) 80 (27%)***

ACR70 3 (1%) 37 (12%)***

EULAR response 44 (22%) 193 (65%)***(good/moderate)

Mean change in DAS -0.34 -1.83***† Outcome at 24 weeks

Significant difference from placebo + MTX at the primary timepoint: ***p ≤ 0.0001

Patients treated with rituximab in combination with methotrexate had a significantly greater reductionin disease activity score (DAS28) than patients treated with methotrexate alone (Table 15). Similarly,a good to moderate European League Against Rheumatism (EULAR) response was achieved bysignificantly more rituximab treated patients treated with rituximab and methotrexate compared topatients treated with methotrexate alone (Table 15).

Structural joint damage was assessed radiographically and expressed as change in modified Total

Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.

In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitortherapies, receiving rituximab in combination with methotrexate demonstrated significantly lessradiographic progression than patients originally receiving methotrexate alone at 56 weeks. Of thepatients originally receiving methotrexate alone, 81% received rituximab either as rescue betweenweeks 16-24 or in the extension trial, before Week 56. A higher proportion of patients receiving theoriginal rituximab/MTX treatment also had no erosive progression over 56 weeks (Table 16).

Table 16 Radiographic outcomes at 1 year (mITT population)

Placebo+MTX Rituximab+MTX2 x 1,000 mg

Trial 1 (n=184) (n=273)

Mean change from baseline:

Modified total sharp score 2.30 1.01*

Erosion score 1.32 0.60*

Joint space narrowing score 0.98 0.41**

Proportion of patients with no 46% 53%, NSradiographic change

Proportion of patients with no erosive 52% 60%, NSchange150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX byone year * p < 0.05, ** p < 0.001. Abbreviation: NS, non-significant

Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysisat 2 years in Trial 1 demonstrated significantly reduced progression of structural joint damage inpatients receiving rituximab in combination with methotrexate compared to methotrexate alone as wellas a significantly higher proportion of patients with no progression of joint damage over the 2-yearperiod.

Significant reductions in disability index (HAQ-DI) and fatigue (FACIT-Fatigue) scores wereobserved in patients treated with rituximab compared to patients treated with methotrexate alone. Theproportions of rituximab treated patients showing a minimal clinically important difference (MCID) in

HAQ-DI (defined as an individual total score decrease of > 0.22) was also higher than among patientsreceiving methotrexate alone (Table 17).

Significant improvement in health-related quality of life was also demonstrated with significantimprovement in both the physical health score (PHS) and mental health score (MHS) of the SF-36.

Further, significantly higher proportion of patients achieved MCIDs for these scores (Table 17).

Table 17 Physical function and quality of life outcomes at Week 24 in Trial 1

Outcome† Placebo+MTX Rituximab+MTX(2 x 1,000 mg)n=201 n=298

Mean change in HAQ-DI 0.1 -0.4***% HAQ-DI MCID 20% 51%

Mean change in FACIT-T -0.5 -9.1***n=197 n=294

Mean change in SF-36 PHS 0.9 5.8***% SF-36 PHS MCID 13% 48%***

Mean change in SF-36 MHS 1.3 4.7**% SF-36 MHS MCID 20% 38%*† Outcome at 24 weeks

Significant difference from placebo at the primary time point: * p < 0.05, ** p < 0.001, *** p ≤ 0.0001

MCID HAQ-DI ≥ 0.22, MCID SF-36 PHS > 5.42, MCID SF-36 MHS > 6.33

Patients seropositive to Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide (anti-CCP)who were treated with rituximab in combination with methotrexate showed an enhanced responsecompared to patients negative to both.

Efficacy outcomes in rituximab treated patients were analysed based on autoantibody status prior tocommencing treatment. At Week 24, patients who were seropositive to RF and/or anti-CCP at baselinehad a significantly increased probability of achieving ACR20 and 50 responses compared toseronegative patients (p=0.0312 and p=0.0096) (Table 18). These findings were replicated at Week 48,where autoantibody seropositivity also significantly increased the probability of achieving ACR70. Atweek 48 seropositive patients were 2-3 times more likely to achieve ACR responses compared toseronegative patients. Seropositive patients also had a significantly greater decrease in DAS28-ESRcompared to seronegative patients (Figure 1).

Table 18 Summary of efficacy by baseline autoantibody status

Week 24 Week 48

Seropositive Seronegative Seropositive Seronegative(n=514) (n=106) (n=506) (n=101)

ACR20 (%) 62.3* 50.9 71. 1* 51.5

ACR50 (%) 32.7* 19.8 44.9** 22.8

ACR70 (%) 12.1 5.7 20.9* 6.9

EULAR response (%) 74.8* 62.9 84.3* 72.3

Mean change DAS28- -1.97** -1.50 -2.48*** -1.72

ESR

Significance levels were defined as * p <0.05, ** p < 0.001, *** p < 0.0001.

Figure 1: Change from baseline of DAS28-ESR by baseline autoantibody status

Treatment with rituximab in combination with methotrexate over multiple courses resulted insustained improvements in the clinical signs and symptoms of RA, as indicated by ACR, DAS28-ESRand EULAR responses which was evident in all patient populations studied (Figure 2). Sustainedimprovement in physical function as indicated by the HAQ-DI score and the proportion of patientsachieving MCID for HAQ-DI were observed.

Figure 2: ACR responses for 4 treatment courses (24 weeks after each course (within patient,within visit) in patients with an inadequate response to TNF-inhibitors (n=146)

A total of 392/3 095 (12.7%) patients with rheumatoid arthritis tested positive for ADA in clinicalstudies following therapy with rituximab. The emergence of ADA was not associated with clinicaldeterioration or with an increased risk of reactions to subsequent infusions in the majority of patients.

The presence of ADA may be associated with worsening of infusion or allergic reactions after thesecond infusion of subsequent courses.

The European Medicines Agency has waived the obligation to submit the results of studies withrituximab in all subsets of the paediatric population with autoimmune arthritis. See section 4.2 forinformation on paediatric use.

Clinical efficacy and safety in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis(MPA)

Adult induction of remission treatment

In GPA/MPA Study 1, a total of 197 patients aged 15 years or older with severe, active GPA (75%)and MPA (24%) were enrolled and treated in an active-comparator, randomised, double-blind,multicentre, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2 mg/kg/day)for 3-6 months or rituximab (375 mg/m2) once weekly for 4 weeks. All patients in thecyclophosphamide arm received azathioprine maintenance therapy in during follow-up. Patients inboth arms received 1,000 mg of pulse intravenous methylprednisolone (or another equivalent-doseglucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding80 mg/day). Prednisone tapering was to be completed by 6 months from the start of trial treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a

Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and offglucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%.

The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission (CR)at 6 months (Table 19).

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsingdisease (Table 20).

Table 19 Percentage of adult patients who achieved complete remission at 6 months(Intent -to-treat population*)

Rituximab (n=99) Cyclophosphamide Treatment difference(n=98) (rituximab-cyclophosphamide)10.6%

Rate 63.6% 53.1% 95.1%b CI (-3.2%,24.3%)a− CI = confidence interval.− * Worst case imputationa Non-inferiority was demonstrated since the lower bound (-3.2%) was higher than the pre-determined non-inferiority margin (-20%).b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacyanalysis.

Table 20 Complete remission at 6-months by disease status

Rituximab Cyclophosphamide Difference (CI 95%)

All patients n=99 n=98

Newly diagnosed n=48 n=48

Relapsing n=51 n=50

Complete remission

All patients 63.6% 53.1% 10.6% (-3.2, 24.3)

Newly diagnosed 60.4% 64.6% -4.2% (-23.6, 15.3)

Relapsing 66.7% 42.0% 24.7% (5.8, 43.6)

Worst case imputation is applied for patients with missing data

In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved CRat 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance ofcomplete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at18 months. From Month 12 to Month 18, 8 relapses were observed in the rituximab group comparedwith four in the cyclophosphamide group.

A total of 23/99 (23%) rituximab-treated patients from the induction of remission trial tested positivefor ADA by 18 months. None of the 99 rituximab-treated patients were ADA positive at screening.

There was no apparent trend or negative impact of the presence of ADA on safety or efficacy in theinduction of remission trial.

Adult maintenance of remission treatment

A total of 117 patients (88 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associatedvasculitis) in disease remission were randomised to receive azathioprine (59 patients) or rituximab(58 patients) in a prospective, multi-centre, controlled, open-label study. Included patients were 21 to75 years of age and had newly diagnosed or relapsing disease in complete remission after combinedtreatment with glucocorticoids and pulse cyclophosphamide. The majority of patients were ANCA-positive at diagnosis or during the course of their disease; had histologically confirmed necrotizingsmall-vessel vasculitis with a clinical phenotype of GPA or MPA, or renal limited ANCA-associatedvasculitis; or both.

Remission-induction therapy included IV prednisone, administered as per the investigator’s discretion,preceded in some patients by methylprednisolone pulses, and pulse cyclophosphamide until remissionwas attained after 4 to 6 months. At that time, and within a maximum of 1 month after the lastcyclophosphamide pulse, patients were randomly assigned to receive either rituximab (two 500 mgintravenous infusions separated by two weeks (on Day 1 and Day 15) followed by 500 mg IV every6 months for 18 months) or azathioprine (administered orally at a dose of 2 mg/kg/day for 12 months,then 1.5 mg/kg/day for 6 months, and finally 1 mg/kg/day for 4 months [treatment discontinuationafter these 22 months]). Prednisone treatment was tapered and then kept at a low dose (approximately5 mg per day) for at least 18 months after randomisation. Prednisone dose tapering and the decision tostop prednisone treatment after Month 18 were left at the investigator’s discretion.

All patients were followed until Month 28 (10 or 6 months, respectively, after the last rituximabinfusion or azathioprine dose). Pneumocystis jirovecii pneumonia prophylaxis was required for allpatients with CD4+ T-lymphocyte counts less than 250 per cubic millimetre.

The primary outcome measure was the rate of major relapse at Month 28.

At Month 28, major relapse (defined by the reappearance of clinical and/or laboratory signs ofvasculitis activity ([BVAS] > 0) that could lead to organ failure or damage or could be lifethreatening) occurred in 3 patients (5%) in the rituximab group and 17 patients (29%) in theazathioprine group (p=0.0007). Minor relapses (not life threatening and not involving major organdamage) occurred in seven patients in the rituximab group (12%) and eight patients in the azathioprinegroup (14%).

The cumulative incidence rate curves showed that time to first major relapse was longer in patientswith rituximab starting from Month 2 and was maintained up to Month 28 (Figure 3).

Figure 3: Cumulative incidence over time of first major relapse

Percentage of

Patientswith

First

Major

Relapse

Survival Time (Months)

Number of Subjects with Major Relapse

Azathioprine 0 0 3 3 5 5 8 8 9 9 9 10 13 15 17

Rituximab 0 0 0 0 1 1 1 1 1 1 1 1 3 3 3

Number of subjects at risk

Azathioprine 59 56 52 50 47 47 44 44 42 41 40 39 36 34 0

Rituximab 58 56 56 56 55 54 54 54 54 54 54 54 52 50 0

Note: Patients were censored at Month 28 if they had no event.

A total of 6/34 (18%) of rituximab treated patients from the maintenance therapy clinical trialdeveloped ADA. There was no apparent trend or negative impact of the presence of ADA on safety orefficacy in the maintenance therapy clinical trial.

Study WA25615 (PePRS) was a multicentre, open-label, single-arm, uncontrolled study in25 paediatric patients (≥ 2 to < 18 years old) with severe, active GPA or MPA. The median age ofpatients in the study was: 14 years (range: 6-17 years) and the majority of patients (20/25 [80%]) werefemale. A total of 19 patients (76%) had GPA and 6 patients (24%) had MPA at baseline. Eighteenpatients (72%) had newly diagnosed disease upon study entry (13 patients with GPA and 5 patientswith MPA) and 7 patients had relapsing disease (6 patients with GPA and 1 patient with MPA).

The study design consisted of an initial 6-month remission induction phase, with a minimum 18-month follow-up, up to a maximum of 54 months (4.5 years) overall. Patients were to receive aminimum of 3 doses of IV methylprednisolone (30 mg/kg/day, not exceeding 1 g/day) prior to the firstrituximab intravenous infusion. If clinically indicated, additional daily doses (up to three), of IVmethylprednisolone could be given. The remission induction regimen consisted of four once weeklyintravenous infusions of rituximab at a dose of 375 mg/m2 BSA, on study days 1, 8, 15 and 22 incombination with oral prednisolone or prednisone at 1 mg/kg/day (max 60 mg/day) tapered to0.2 mg/kg/day minimum (max 10 mg/day) by Month 6. After the remission induction phase, patientscould, at the discretion of the investigator, receive subsequent rituximab infusions on or after Month 6to maintain PVAS remission and control disease activity (including progressive disease or flare) or toachieve first remission.

All 25 patients completed all four once weekly intravenous infusions for the 6-month remissioninduction phase. A total of 24 out of 25 patients completed at least 18 months of follow-up.

The objectives of this study were to evaluate safety, PK parameters, and efficacy of rituximab inpaediatric GPA and MPA patients (≥ 2 to < 18 years old). The efficacy objectives of the study wereexploratory and principally assessed using the Paediatric Vasculitis Activity Score (PVAS) (Table 21).

Twenty-four out of 25 patients (96%) in Study WA25615 achieved oral glucocorticoid taper to0.2 mg/kg/day (or less than or equal to 10 mg/day, whichever was lower) at or by Month 6 during theprotocol-defined oral steroid taper.

A decrease in median overall oral glucocorticoid use was observed from Week 1 (median = 45 mgprednisone equivalent dose [IQR: 35 - 60]) to Month 6 (median = 7.5 mg [IQR: 4-10]), which wassubsequently maintained at Month 12 (median = 5 mg [IQR: 2-10]) and Month 18 (median = 5 mg[IQR: 1-5]).

During the Overall Study Period, patients received between 4 and 28 infusions of rituximab (up to4.5 yrs [53.8 months]). Patients received up to 375 mg/m2 x 4 of rituximab, approximately every6 months at the discretion of the investigator. In total, 17 out of 25 patients (68%) received additionalrituximab treatment at or post Month 6 until the Common Close Out, 14 out of these 17 patientsreceived additional rituximab treatment between Month 6 and Month 18.

Table 21 Study WA25615 (PePRS) - PVAS Remission at Month 1, 2, 4, 6, 12 and 18

Study visit Number of Responders in PVAS Remission* 95% CIα(response rate [%])n=25

Month 1 0 0.0%, 13.7%

Month 2 1 (4.0%) 0.1%, 20.4%

Month 4 5 (20.0%) 6.8%, 40.7%

Month 6 13 (52.0%) 31.3%, 72.2%

Month 12 18 (72.0%) 50.6%, 87.9%

Month 18 18 (72.0%) 50.6%, 87.9%

* PVAS of 0 and achieved glucocorticoid taper to 0.2 mg/kg/day (or 10 mg/day, whichever is lower) atthe assessment time-point.α the efficacy results are exploratory and no formal statistical testing was performed for these endpointsrituximab, treatment (375 mg/m2 x 4 infusions) up to Month 6 was identical for all patients. Follow-uptreatment post Month 6 was at the discretion of the investigator.

A total of 4/25 patients (16%) developed ADA during the overall study period. Limited data showsthere was no trend observed in the adverse reactions reported in ADA positive patients.

There was no apparent trend or negative impact of the presence of ADA on safety or efficacy in thepaediatric GPA and MPA clinical trials.

The European Medicines Agency has waived the obligation to submit the results of studies withrituximab in paediatric population < 2 years of age in severe, active GPA or MPA. See section 4.2 forinformation on paediatric use.

Clinical efficacy and safety in pemphigus vulgaris (PV)

The efficacy and safety of rituximab in combination with short-term, low-dose glucocorticoid(prednisone) therapy were evaluated in newly diagnosed patients with moderate to severe pemphigus(74 PV and 16 pemphigus foliaceus [PF]) in this randomised, open-label, controlled, multicentrestudy. Patients were between 19 and 79 years of age and had not received prior therapies forpemphigus. In the PV population, 5 (13%) patients in the rituximab group and 3 (8%) patients in thestandard prednisone group had moderate disease and 33 (87%) patients in the rituximab group and 33(92%) patients in the standard-dose prednisone group had severe disease according to disease severitydefined by Harman’s criteria.

Patients were stratified by baseline disease severity (moderate or severe) and randomised 1:1 toreceive either rituximab and low-dose prednisone or standard-dose prednisone. Patients randomised tothe rituximab group received an initial intravenous infusion of 1000 mg rituximab on Study Day 1 incombination with 0.5 mg/kg/day oral prednisone tapered off over 3 months if they had moderatedisease or 1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease, and asecond intravenous infusion of 1000 mg on Study Day 15. Maintenance infusions of rituximab 500 mgwere administered at Months 12 and 18. Patients randomised to the standard-dose prednisone groupreceived an initial 1 mg/kg/day oral prednisone tapered off over 12 months if they had moderatedisease or 1.5 mg/kg/day oral prednisone tapered off over 18 months if they had severe disease.

Patients in the rituximab group who relapsed could receive an additional infusion of rituximab1000 mg in combination with reintroduced or escalated prednisone dose. Maintenance and relapseinfusions were administered no sooner than 16 weeks following the previous infusion.

The primary objective for the study was complete remission (complete epithelialisation and absence ofnew and/or established lesions) at Month 24 without the use of prednisone therapy for two months ormore (CRoff for  2 months).

The study showed statistically significant results of rituximab and low-dose prednisone over standard-dose prednisone in achieving CRoff  2 months at Month 24 in PV patients (see Table 22).

Table 22 Percentage of PV patients who achieved complete remission off corticosteroidtherapy for two months or more at Month 24 (Intent-to-Treat Population - PV)

Rituximab + Prednisone

Prednisone N=36 p-value a 95% CIb

N=38

Number of responders 34 (89.5%) 10 (27.8%) < 0.0001 61.7% (38.4, 76.5)(response rate [%])ap-value is from Fisher’s exact test with mid-p correctionb 95% confidence interval is corrected Newcombe interval

The number of rituximab plus low-dose prednisone patients off prednisone therapy or on minimaltherapy (prednisone dose of 10 mg or less per day) compared to standard-dose prednisone patientsover the 24-month treatment period shows a steroid-sparing effect of rituximab (Figure 4).

Figure 4: Number of patients who were off or on minimal corticosteroid (≤ 10 mg/day)therapy over time

A total of 19/34 (56%) patients with PV, who were treated with rituximab, tested positive for ADAantibodies by 18 months. The clinical relevance of ADA formation in rituximab-treated PV patients isunclear.

In a randomised, double-blind, double-dummy, active-comparator, multicentre study, the efficacy andsafety of rituximab compared with mycophenolate mofetil (MMF) were evaluated in patients withmoderate-to-severe PV receiving 60-120 mg/day oral prednisone or equivalent (1.0-1.5 mg/kg/day) atstudy entry and tapered to reach a dose of 60 or 80 mg/day by Day 1. Patients had a confirmeddiagnosis of PV within the previous 24 months and evidence of moderate-to-severe disease (defined asa total Pemphigus Disease Area Index, PDAI, activity score of  15).

One hundred and thirty-five patients were randomised to treatment with rituximab 1000 mgadministered on Day 1, Day 15, Week 24 and Week 26 or oral MMF 2 g/day for 52 weeks incombination with 60 or 80 mg oral prednisone with the aim of tapering to 0 mg/day prednisone by

Week 24.

The primary efficacy objective for this study was to evaluate at Week 52, the efficacy of rituximabcompared with MMF in achieving sustained complete remission defined as achieving healing oflesions with no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone orequivalent, and maintaining this response for at least 16 consecutive weeks, during the 52-weektreatment period.

The study demonstrated the superiority of rituximab over MMF in combination with a tapering courseof oral corticosteroids in achieving CRoff corticosteroid  16 weeks at Week 52 in PV patients(Table 23).The majority of patients in the mITT population were newly diagnosed (74%) and 26% ofpatients had established disease (duration of illness  6 months and received prior treatment for PV).

Table 23 Percentage of PV patients who achieved sustained complete remission offcorticosteroid therapy for 16 weeks or more at Week 52 (Modified Intent-to-Treat

Population)

Rituximab MMF Difference (95% CI) p-value(N=62) (N=63)

Number of responders 25 (40.3%) 6 (9.5%) 30.80% (14.70%, 45.15%) < 0.0001(response rate [%])

Newly diagnosed patients 19 (39.6%) 4 (9.1%)

Patients with established 6 (42.9%) 2 (10.5%)disease

MMF = Mycophenolate mofetil. CI = Confidence Interval.

Newly diagnosed patients = duration of illness < 6 months or no prior treatment for PV.

Patients with established disease = duration of illness  6 months and received prior treatment for PV.

Cochran-Mantel-Haenszel test is used for p-value.

The analysis of all secondary parameters (including cumulative oral corticosteroid dose, the totalnumber of disease flares, and change in health-related quality of life, as measured by the Dermatology

Life Quality Index) verified the statistically significant results of rituximab compared to MMF.

Testing of secondary endpoints were controlled for multiplicity.

The cumulative oral corticosteroid dose was significantly lower in patients treated with rituximab. Themedian (min, max) cumulative prednisone dose at Week 52 was 2775 mg (450, 22180) in therituximab group compared to 4005 mg (900, 19920) in the MMF group (p=0.0005).

The total number of disease flares was significantly lower in patients treated with rituximab comparedto MMF (6 vs. 44, p< 0.0001) and there were fewer patients who had at least one disease flare (8.1%vs. 41.3%).

By Week 52, a total of 20/63 (31.7%) (19 treatment-induced and 1 treatment-enhanced) rituximab -treated PV patients tested positive for ADA. There was no apparent negative impact of the presence of

ADA on safety or efficacy in PV Study 2.

Adult non-Hodgkin’s lymphoma (NHL)

Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multipleinfusions of rituximab as a single agent or in combination with CHOP therapy (applied rituximabdoses ranged from 100 to 500 mg/m2), the typical population estimates of nonspecific clearance (CL1),specific clearance (CL2) likely contributed by B-cells or tumour burden, and central compartmentvolume of distribution (V1) were 0.14 L/day, 0.59 L/day, and 2.7 L, respectively. The estimatedmedian terminal elimination half-life of rituximab was 22 days (range, 6.1 to 52 days). Baseline

CD19-positive cell counts and size of measurable tumour lesions contributed to some of the variabilityin CL2 of rituximab in data from 161 patients given 375 mg/m2 as an intravenous infusion for4 weekly doses. Patients with higher CD19-positive cell counts or tumour lesions had a higher CL2.

However, a large component of inter-individual variability remained for CL2 after correction for

CD19-positive cell counts and tumour lesion size. V1 varied by body surface area (BSA) and CHOPtherapy. This variability in V1 (27.1% and 19.0%) contributed by the range in BSA (1.53 to 2.32 m2)and concurrent CHOP therapy, respectively, were relatively small. Age, gender and WHOperformance status had no effect on the pharmacokinetics of rituximab. This analysis suggests thatdose adjustment of rituximab with any of the tested covariates is not expected to result in a meaningfulreduction in its pharmacokinetic variability.

Rituximab, administered as an intravenous infusion at a dose of 375 mg/m2 at weekly intervals for4 doses to 203 patients with NHL naive to rituximab, yielded a mean Cmax following the fourthinfusion of 486 µg/mL (range, 77.5 to 996.6 µg/mL). Rituximab was detectable in the serum ofpatients 3 to 6 months after completion of last treatment.

Upon administration of rituximab at a dose of 375 mg/m2 as an intravenous infusion at weeklyintervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusion,spanning from a mean of 243 µg/mL (range, 16 - 582 µg/mL) after the first infusion to 550 µg/mL(range, 171-1 177 µg/mL) after the eighth infusion.

The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 incombination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

In the clinical trial studying paediatric DLBCL/BL/BAL/BLL, the PK was studied in a subset of35 patients aged 3 years and older. The PK was comparable between the two age groups (≥ 3 to< 12 years vs. ≥ 12 to < 18 years). After two rituximab intravenous infusions of 375 mg/m2 in each ofthe two induction cycles (Cycle 1 and 2) followed by one rituximab intravenous infusion of375 mg/m2 in each of the consolidation cycles (Cycle 3 and 4) the maximum concentration washighest after the fourth infusion (Cycle 2) with a geometric mean of 347 μg/mL followed by lowergeometric mean maximum concentrations thereafter (Cycle 4: 247 μg/mL). With this dose regimen,trough levels were sustained (geometric means: 41.8 μg/mL (pre-dose Cycle 2; after 1 cycle),67.7 μg/mL (pre-dose Cycle 3, after 2 cycles) and 58.5 μg/mL (pre-dose Cycle 4, after 3 cycles)). Themedian elimination half-life in paediatric patients aged 3 years and older was 26 days.

The PK characteristics of rituximab in paediatric patients with DLBCL/BL/BAL/BLL were similar towhat has been observed in adult NHL patients.

No PK data are available in the ≥ 6 months to < 3 years age group, however, population PK predictionsupports comparable systemic exposure (AUC, Ctrough) in this age group compared to ≥ 3 years(Table 24). Smaller baseline tumour size is related to higher exposure due to lower time dependentclearance, however, systemic exposures impacted by different tumour sizes remain in the range ofexposure that was efficacious and had an acceptable safety profile.

Table 24 Predicted PK Parameters following the Rituximab Dosing Regimen in Paediatric

DLBCL/BL/BAL/BLL

Age group ≥ 6 mo to < 3 years ≥ 3 to < 12 years ≥ 12 to < 18 years

Ctrough (µg/mL) 47.5 (0.01-179) 51.4 (0.00-182) 44.1 (0.00-149)

AUC1-4 cycles 13501 (278-31070) 11609 (135-31157) 11467 (110-27066)(µg*day/mL)

Results are presented as median (min - max); Ctrough is pre-dose Cycle 4.

Rituximab was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLLpatients. The mean Cmax (N=15) was 408 µg/mL (range, 97 - 764 µg/mL) after the fifth 500 mg/m2infusion and the mean terminal half-life was 32 days (range, 14 - 62 days).

Following two intravenous infusions of rituximab at a dose of 1,000 mg, two weeks apart, the meanterminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day(range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 L(range, 1.7 to7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemicclearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysisrevealed that BSA and gender were the most significant covariates to explain inter-individualvariability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volumeof distribution and a faster clearance than female subjects. The gender-related pharmacokineticdifferences are not considered to be clinically relevant and dose adjustment is not required. Nopharmacokinetic data are available in patients with hepatic or renal impairment.

The pharmacokinetics of rituximab were assessed following two intravenous doses of 500 mg and1,000 mg on days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were doseproportional over the limited dose range studied. Mean Cmax for serum rituximab following firstinfusion ranged from 157 to 171 μg/mL for 2 x 500 mg dose and ranged from 298 to 341 μg/mL for2 x 1,000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 μg/mL for the2 x 500 mg dose and ranged from 355 to 404 μg/mL for the 2 x 1,000 mg dose. Mean terminalelimination half-life ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days forthe 2 x 1,000 mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared tothe first infusion for both doses.

The pharmacokinetics of rituximab were assessed following two intravenous doses of 500 mg and1,000 mg upon re-treatment in the second course. Mean Cmax for serum rituximab following firstinfusion was 170 to 175 μg/mL for 2 x 500 mg dose and 317 to 370 μg/mL for 2 x 1,000 mg dose.

Cmax following second infusion, was 207 μg/mL for the 2 x 500 mg dose and ranged from377 to 386 μg/mL for the 2 x 1,000 mg dose. Mean terminal elimination half-life after the secondinfusion, following the second course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 daysfor the 2 x 1,000 mg dose. PK parameters for rituximab were comparable over the two treatmentcourses.

The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following thesame dose regimen (2 x 1,000 mg, intravenous, 2 weeks apart), were similar with a mean maximumserum concentration of 369 μg/mL and a mean terminal half-life of 19.2 days.

Adult population

Based on the population pharmacokinetic analysis of data in 97 patients with GPA and MPA whoreceived 375 mg/m2 rituximab once weekly for four doses, the estimated median terminal eliminationhalf-life was 23 days (range, 9 - 49 days).

Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 - 0.726 L/day)and 4.50 L (range 2.25 - 7.39 L) respectively. Maximum concentration during the first 180 days(Cmax), minimum concentration at Day 180 (C180) and Cumulative area under the curve over 180 days(AUC180) were (median [range]) 372.6 (252.3-533.5) μg/mL, 2.1 (0-29.3) μg/mL and 10302 (3653-21874) μg/mL*days, respectively. The PK parameters of rituximab in adult GPA and MPA patientsappear similar to what has been observed in rheumatoid arthritis patients.

Based on the population pharmacokinetic analysis of 25 children (6-17 years old) with GPA and MPAwho received 375 mg/m2 rituximab once weekly for four doses, the estimated median terminalelimination half-life was 22 days (range, 11 to 42 days). Rituximab mean clearance and volume ofdistribution were 0.221 L/day (range, 0. 0996 to 0.381 L/day) and 2.27 L (range 1.43 to 3.17 L)respectively. Maximum concentration during the first 180 days (Cmax), minimum concentration at

Day 180 (C180) and Cumulative area under the curve over 180 days (AUC180) were (median [range])382.8 (270.6-513.6) μg/mL, 0.9 (0-17.7) μg/mL and 9787 (4838-20446) μg/mL*day, respectively. The

PK parameters of rituximab in paediatric patients with GPA or MPA were similar to those in adultswith GPA or MPA, once taking into account the BSA effect on clearance and volume of distributionparameters.

The PK parameters in adult PV patients receiving rituximab 1000 mg at Days 1, 15, 168 and 182 aresummarised in Table 25.

Table 25 Population PK in adult PV patients from PV Study 2

Parameter Infusion cycle1st cycle of 1000 mg 2nd cycle of 1000 mg

Day 1 and Day 15 Day 168 and Day 182

N=67 N=67

Terminal half-life (days)

Median 21.0 26.5(Range) (9.3-36.2) (16.4-42.8)

Clearance (L/day)

Mean 391 247(Range) (159-1510) (128-454)

Central volume of distribution (L)

Mean 3.52 3.52(Range) (2.48-5.22) (2.48-5.22)

Following the first two rituximab administrations (at Day 1 and 15, corresponding to cycle 1), the PKparameters of rituximab in patients with PV were similar to those in patients with GPA/MPA andpatients with RA. Following the last two administrations (at Day 168 and 182, corresponding to cycle2), rituximab clearance decreased while the central volume of distribution remained unchanged.

Rituximab has shown to be highly specific to the CD20 antigen on B-cells. Toxicity studies incynomolgus monkeys have shown no other effect than the expected pharmacological depletion of B-cells in peripheral blood and in lymphoid tissue.

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetusdue to rituximab. However, dose-dependent pharmacologic depletion of B-cells in the lymphoidorgans of the foetuses was observed, which persisted postnatally and was accompanied by a decreasein IgG level in the newborn animals affected. B-cell counts returned to normal in these animals within6 months of birth and did not compromise the reaction to immunisation.

Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevantfor this molecule. No long-term animal studies have been performed to establish the carcinogenicpotential of rituximab.

Specific studies to determine the effects of rituximab on fertility have not been performed. In generaltoxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males orfemales were observed.

Sodium citrate (E331)

Polysorbate 80 (E433)

Sodium chloride

Sodium hydroxide (for pH adjustment) (E524)

Hydrochloric acid (for pH adjustment) (E507)

Water for injections

No incompatibilities between Rixathon and polyvinyl chloride or polyethylene bags or infusion setshave been observed.

The medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years at 2 °C - 8 °C.

Rixathon may be stored at temperatures up to a maximum of 30 °C for a single period of up to 7 days,but not exceeding the original expiry date. The new expiry date must be written on the carton. Uponremoval from refrigerated storage, Rixathon must not be returned to refrigerated storage.

* After aseptic dilution in sodium chloride solution:

Chemical and physical stability of Rixathon diluted in sodium chloride 9 mg/ml (0.9%) solution forinjection has been demonstrated for:

* 30 days at 2 °C - 8 °C and subsequently 24 hours at room temperature (≤ 25 °C)or

* 7 days at ≤ 30 °C, while protected from light.

* After aseptic dilution in glucose solution:

Chemical and physical stability of Rixathon diluted in 5% glucose solution has been demonstrated for24 hours at 2 °C - 8 °C and subsequently 12 hours at room temperature (≤ 25 °C).

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

Store in a refrigerator (2 °C - 8 °C).

Do not freeze. Keep the vial in the outer carton in order to protect from light.

For storage conditions of the unopened vial outside the refrigerator, see section 6.3.

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

10 mL vial: Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in10 mL. Packs of 2 or 3 vials.

50 mL vial: Clear Type I glass vials with butyl rubber stopper containing 500 mg of rituximab in50 mL. Packs of 1 or 2 vials.

Not all pack sizes may be marketed.

Rixathon is provided in sterile, preservative-free, non-pyrogenic, single use vials. Use a sterile needleand syringe to prepare Rixathon.

Aseptically withdraw the necessary amount of Rixathon, and dilute to a calculated concentration of1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride9 mg/mL (0.9%) solution for injection or 5% D-Glucose in water. For mixing the solution, gentlyinvert the bag in order to avoid foaming. Care must be taken to ensure the sterility of preparedsolutions. Since the medicinal product does not contain any anti-microbial preservative orbacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should beinspected visually for particulate matter and discolouration prior to administration.

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

Sandoz GmbH

Biochemiestr. 106250 Kundl

Austria

EU/1/17/1185/001

EU/1/17/1185/002

EU/1/17/1185/003

EU/1/17/1185/004

Date of first authorisation: 15 June 2017

Date of latest renewal: 24 February 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.