TRUXIMA 100mg perfusive solution concentrate medication leaflet

Truxima 100 mg concentrate for solution for infusion

Truxima 500 mg concentrate for solution for infusion

Truxima 100 mg concentrate for solution for infusion

Each mL contains 10 mg of rituximab.

Each 10 mL vial contains 100 mg of rituximab.

Truxima 500 mg concentrate for solution for infusion

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 and heavy-chainvariable region sequences. The antibody is produced by mammalian (Chinese hamster ovary) cellsuspension culture and purified by affinity chromatography and ion exchange, including specific viralinactivation and removal procedures.

Polysorbates

Each 10 mL vial contains 7 mg of polysorbate 80.

Each 50 mL vial contains 35 mg of polysorbate 80.

Each 10 mL vial contains 2.3 mmol (52. 6 mg) sodium.

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

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear, colourless liquid with pH of 6.3 - 6.8 and osmolality of 329 - 387 mOsmol/kg.

Truxima is indicated in adults for the following indications:

Truxima is indicated for the treatment of previously untreated adult patients with stage III-IV follicularlymphoma in combination with chemotherapy.

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

Truxima monotherapy is indicated for treatment of adult patients with stage III-IV follicular lymphomawho are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Truxima is indicated for the treatment of adult patients with CD20 positive diffuse large B-cellnon-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine,prednisolone) chemotherapy.

Truxima in combination with chemotherapy is indicated for the treatment of paediatric patients (aged ≥ 6months to < 18 years old) with previously untreated advanced stage CD20 positive diffuse large B-celllymphoma (DLBCL), Burkitt lymphoma (BL)/Burkitt leukaemia (mature B-cell acute leukaemia) (BAL)or Burkitt-like lymphoma (BLL).

Truxima in combination with chemotherapy is indicated for the treatment of patients with previouslyuntreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for patientspreviously treated with monoclonal antibodies including Truxima or patients refractory to previous

Truxima plus chemotherapy.

See section 5.1 for further information.

Truxima 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 medicinal product (DMARD) including one or more tumour necrosisfactor (TNF) inhibitor therapies.

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

Granulomatosis with polyangiitis and microscopic polyangiitis

Truxima, in combination with glucocorticoids, is indicated for the treatment of adult patients with severe,active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA).

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

Truxima is indicated for the treatment of patients with moderate to severe pemphigus vulgaris (PV).

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

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

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

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

In paediatric patients with non-Hodgkin’s lymphoma, premedication with paracetamol and H1antihistamine (= diphenhydramine or equivalent) should be administered 30 to 60 minutes before the startof the infusion of rituximab. In addition, prednisone should be given as indicated in Table 1.

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start oftherapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patientswhose lymphocyte counts are > 25 x 109/L it is recommended to administer prednisone/prednisolone100 mg intravenous shortly before infusion with rituximab to decrease the rate and severity of acuteinfusion reactions and/or cytokine release syndrome.

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

In adult patients with GPA or MPA, methylprednisolone given intravenously for 1 to 3 days at a dose of1000 mg per day is recommended prior to the first infusion of rituximab (the last dose ofmethylprednisolone may be given on the same day as the first infusion of rituximab). 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 rituximab treatment.

Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for adult patients with GPA/MPA or

PV during and following rituximab treatment, as appropriate according to local clinical practice guidelines.

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

Following completion of intravenous methylprednisolone administration, patients should receive oralprednisone 1 mg/kg/day (not to exceed 60 mg/day) and tapered as rapidly as possible per clinical need (seesection 5.1).

Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for paediatric patients with GPA or

MPA during and following rituximab treatment, as appropriate.

Non-Hodgkin’s lymphoma

The recommended dose of rituximab 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.

Rituximab 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 rituximab 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 rituximab used as a maintenance treatment for patients withrelapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m2 bodysurface area once every 3 months (starting 3 months after the last dose of induction therapy) until diseaseprogression or for a maximum period of two years (8 infusions in total).

* Relapsed/refractory follicular lymphoma

The recommended dose of rituximab monotherapy used as induction treatment for adult patients with stage

III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse afterchemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly forfour weeks.

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

Adult diffuse large B cell non-Hodgkin's lymphoma

Rituximab should be used in combination with CHOP chemotherapy. The recommended dosage is 375mg/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 non-Hodgkin’slymphoma.

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

Chronic lymphocytic leukaemia

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

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

A course of rituximab consists of two 1000 mg intravenous infusions. The recommended dosage ofrituximab is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion twoweeks 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 be delayeduntil disease activity returns.

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

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

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

Following induction of remission with rituximab, 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, rituximabmaintenance treatment should be initiated during the 4-week period that follows disease remission.

rituximab 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 receiverituximab 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 rituximab maintenance therapy, up to 5 years.

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

The recommended dosage of rituximab for the treatment of pemphigus vulgaris is 1000 mg administered asan intravenous 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 intravenousshould be administered at months 12 and 18, and then every6 months thereafter if needed, based on clinical evaluation.

Treatment of relapse

In the event of relapse, patients may receive 1000 mg intravenous. The healthcare provider should alsoconsider 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.

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

Non-Hodgkin’s lymphoma

In paediatric patients from ≥ 6 months to < 18 years of age with previously untreated, advanced stage

CD20 positive DLBCL/BL/BAL/BLL, rituximab should be used in combination with systemic Lymphome

Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dosage of rituximab is 375mg/m2

BSA, administered as an intravenous infusion. No rituximab dose adjustments, other than by BSA, arerequired.

The safety and efficacy of rituximab in paediatric patients ≥ 6 months to < 18 years of age has not beenestablished in indications other than previously untreated advanced stage CD20 positive

DLBCL/BL/BAL/BLL. Only limited data are available for patients under 3 years of age. See section 5.1for further information.

Rituximab 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 non-Hodgkin’s lymphoma 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 notgiven at 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 Day 25 to 28 ofcourse 1 (M1) consolidation course 2 Starts when peripheral counts have recovered(CYVE) from consolidation course 2 (CYVE) with ANC>

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

Maintenance Day 28 of maintenance -course 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 non-Hodgkin’s lymphoma paediatric patients: concomitantchemotherapy with rituximab

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 3g/m2 and 2 consolidation courses(CYM)

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 8g/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 dosage of rituximab for induction of remission therapy in paediatric patients with severe,active GPA or MPA is 375 mg/m2 BSA, administered as an intravenous infusion once weekly for 4 weeks.

The safety and efficacy of rituximab in paediatric patients (≥ 2 to < 18 years of age) has not beenestablished in indications other than severe, active GPA or MPA.

Rituximab should not be used in paediatric patients less than 2 years of age with severe, active GPA or

MPA as there is a possibility of an inadequate immune response towards childhood vaccinations againstcommon, vaccine preventable childhood diseases (e.g. measles, mumps, rubella, and poliomyelitis) (seesection 5.1).

Truxima is for intravenous use.

The prepared Truxima solution should be administered as an intravenous infusion through adedicated line. It should not be administered as an intravenous push or bolus.

Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). Patientswho develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia shouldhave the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma 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. Atthis time, the infusion can be initially resumed at not more than one-half the previous rate. If the samesevere adverse reactions occur for a second time, the decision to stop the treatment should be seriouslyconsidered on a case by case basis.

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

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

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

Paediatric patients - non-Hodgkin’s lymphoma

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

Subsequent doses of rituximab can be infused at an initial rate of 1 mg/kg/h (maximum 50 mg/h); it can beincreased 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 signicant 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 1000 mg rituximab administered over the standard infusion schedule, a more rapid infusioncan be administered for second and subsequent infusions using the same concentration as in previousinfusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250 mg/hour for the first 30 minutes andthen 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this infusion schedulecan be used when administering subsequent infusions.

Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous seriousinfusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapidinfusion.

Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

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

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis, microscopicpolyangiitis and pemphigus vulgaris

Hypersensitivity to the active substance or to murine proteins, or to any of the other 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 disease (seesection 4.4 regarding other cardiovascular diseases).

In order to improve traceability of biological medicinal products, the tradename and batch number of theadministered product should be clearly recorded (or stated) in the patient file.

All patients treated with rituximab for rheumatoid arthritis, GPA, MPA or pemphigus vulgaris must begiven the patient alert card with each infusion. The alert card contains important safety information forpatients regarding potential increased risk of infections, including PML.

Very rare cases of fatal PML have been reported following the use of rituximab. Patients must bemonitored at regular intervals for any new or worsening neurological symptoms or signs that may besuggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded.

The clinician should evaluate the patient to determine if the symptoms are indicative of neurologicaldysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with aneurologist should be considered as clinically indicated.

If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid(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 to informtheir partner or caregivers about their treatment, since they may notice symptoms that the patient is notaware of.

If a patient develops PML, the dosing of rituximab must be permanently discontinued.

Following reconstitution of the immune system in immunocompromised patients with PML,stabilisation or improved outcome has been seen. It remains unknown if early detection of PML andsuspension of rituximab therapy may lead to similar stabilisation or improved outcome.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Rituximab 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 of therituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting thefirst rituximab intravenous infusion. They were characterised by pulmonary events and in some casesincluded 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. This syndromemay be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia,hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate dehydrogenase (LDH) and maybe associated with acute respiratory failure and death. The acute respiratory failure may be accompaniedby events such as pulmonary interstitial infiltration or oedema, visible on a chest X-ray. The syndromefrequently manifests itself within one or two hours of initiating the first infusion. Patients with a historyof pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater risk of pooroutcome and should be treated with increased caution. Patients who develop severe cytokine releasesyndrome should have their infusion interrupted immediately (see section 4.2) and should receiveaggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed bydeterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonaryinfiltration have been resolved or ruled out. Further treatment of patients after complete resolution ofsigns and symptoms has rarely resulted in repeated 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 throughout thefirst infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion inthese patients or a split dosing over two days during the first cycle and any subsequent cycles if thelymphocyte count is still > 25 x 109/L.

Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated withrituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10%of patients) see section 4.8. These symptoms are usually reversible with interruption of rituximab infusionand administration of an anti-pyretic, an antihistaminic and occasionally oxygen, intravenous sodiumchloride solution or bronchodilators, and glucocorticoids if required. Please see cytokine releasesyndrome above for 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 rituximab.

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 rituximab administration, consideration should be given towithholding anti-hypertensive medicinal product 12 hours prior to the rituximab infusion.

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardialinfarction have occurred in patients treated with rituximab. Therefore, patients with a history of cardiacdisease and/or cardiotoxic chemotherapy should be monitored closely.

Although rituximab 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. Rituximab has been used in 21 patients who underwentautologous bone marrow transplantation and other risk groups with a presumable reduced bone marrowfunction without inducing myelotoxicity.

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

Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8).

Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsisand opportunistic infections, see section 4.3).

Physicians should exercise caution when considering the use of rituximab in patients with a history ofrecurring or chronic infections or with underlying conditions which may further predispose patients toserious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in subjects receiving rituximab including fulminanthepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic chemotherapy.

Limited information from one study in relapsed/refractory CLL patients suggests that rituximab treatmentmay also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening shouldbe performed in all patients before initiation of treatment with rituximab. At minimum this should include

HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per localguidelines. Patients with active hepatitis B disease should not be treated with rituximab. Patients withpositive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start oftreatment and should be monitored and managed following local medical standards to prevent hepatitis Breactivation.

Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported duringpost-marketing use of rituximab in NHL and CLL (see section 4.8). The majority of patients had receivedrituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant.

Cases of enteroviral meningoencephalitis including fatalities have been reported following useof rituximab.

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.

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

NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated withrituximab may receive non-live vaccinations; however, with non-live vaccines response rates may bereduced. In a non-randomised study, adult patients with relapsed low-grade NHL who received rituximabmonotherapy when compared to healthy untreated controls had a lower rate of response to vaccinationwith tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs.

76% when assessed for >2-fold increase in antibody titer). For CLL patients, similar results are assumableconsidering similarities between both diseases but that has not been 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.

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 asuspected relationship to rituximab, treatment should be permanently discontinued.

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

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

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

Rituximab is associated with infusion-related reactions (IRRs), which may be related to release ofcytokines and/or other chemical mediators.

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the post-marketingsetting. In rheumatoid arthritis most infusion-related events reported in clinical trials were mild tomoderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throatirritation, flushing, rash, urticaria, hypertension and pyrexia. In general, the proportion of patientsexperiencing any infusion reaction was higher following the first infusion than following the secondinfusion of any treatment course. The incidence of IRR decreased with subsequent courses (see section4.8). The reactions reported were usually reversible with a reduction in rate, or interruption, of rituximabinfusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenoussodium chloride solution or bronchodilators, and glucocorticoids if required. Closely monitor patientswith pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions.

Depending on the severity of the IRR and the required interventions, temporarily or permanentlydiscontinue rituximab. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g. from100 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 rituximab.

There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III) orsevere, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence of pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been observed,as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history, and those whoexperienced prior cardiopulmonary adverse reactions, the risk of cardiovascular complications resultingfrom infusion reactions should be considered before treatment with rituximab and patients closelymonitored during administration. Since hypotension may occur during rituximab infusion, considerationshould be given to withholding anti-hypertensive medicinal product 12 hours prior to the rituximabinfusion.

IRRs in patients with GPA, MPA and pemphigus vulgaris were consistent with those seen forrheumatoid arthritis patients in clinical trials and in the post-marketing setting (see section 4.8).

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 should be monitored closely (see Infusion-related reactions, above).

Based on the mechanism of action of rituximab and the knowledge that B cells play an important role inmaintaining normal immune response, patients have an increased risk of infection following rituximabtherapy (see section 5.1). Serious infections, including fatalities, can occur during therapy with rituximab(see section 4.8). Rituximab should not be administered to patients with an active, severe infection (e.g.

tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely immunocompromisedpatients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution whenconsidering the use of rituximab in patients with a history of recurring or chronic infections or withunderlying conditions which may further predispose patients to serious infection, e.g.

hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulin levels aredetermined prior to initiating treatment with rituximab.

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

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported followinguse of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic

Lupus Erythematosus (SLE) and vasculitis.

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

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.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in rheumatoidarthritis, GPA and MPA patients receiving rituximab.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment withrituximab. At minimum this should include HBsAg-status and HBcAb-status. These can be complementedwith other appropriate markers as per local guidelines. Patients with active hepatitis B disease should notbe treated with rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb) shouldconsult liver disease experts before start of treatment and should be monitored and managed followinglocal medical standards to prevent hepatitis B reactivation.

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

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 eventwith a suspected relationship to rituximab, treatment should be permanently discontinued.

Physicians should review the patient’s vaccination status and patients should, if possible, be brought up-to-date with all immunisations in agreement with current immunisation guidelines prior to initiatingrituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration ofrituximab.

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 rituximab or whilstperipherally B cell depleted.

Patients treated with rituximab may receive non-live vaccinations; however, response rates to non-livevaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated with rituximaband methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%), reduced rates topneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal antibody serotypes), and

KLH neoantigen (47% vs. 93%), when given 6 months after rituximab as compared to patients onlyreceiving methotrexate. Should non-live vaccinations be required whilst receiving rituximab therapy, theseshould be completed at least 4 weeks prior to commencing the next course 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 rituximab 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 therapies areused in patients previously treated with rituximab, however patients should be closely observed for signsof infection if biologic agents and/or DMARDs are used following rituximab therapy.

Immunomodulatory medicinal products may increase the risk of malignancy. However, available datado not suggest an increased risk of malignancy for rituximab used in autoimmune indications beyond themalignancy risk already associated with the underlying autoimmune condition.

Polysorbates

This medicine contains 7 mg of polysorbate 80 (E433) in 10 mL vial and 35 mg of polysorbate 80 (E433)in 50 mL vial, which equivalent to 0.7 mg/mL (for 10 mL vial) and 3.5 mg/mL (for 50 mL/vial).

Polysorbates may cause allergic reactions.

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) of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

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 the pharmacokineticsof fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine andcyclophosphamide 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 DMARDfollowing rituximab. In these patients the rate of clinically relevant infection while on rituximab was 6.01per 100 patient years compared to 4.97 per 100 patient years following treatment with 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 rituximab.

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, howevertransient B-cell depletion and lymphocytopenia have been reported in some infants born to mothersexposed to rituximab during pregnancy. Similar effects have been observed in animal studies (see section5.3). For these reasons rituximab should not be administered to pregnant women unless the possiblebenefit 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 describenormal growth and development up to 2years. However, as these data are limited and the long-termoutcomes of breastfed infants remain unknown, breastfeeding is not recommended while beingtreated with rituximab and optimally for 6 months following rituximab treatment.

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

Rituximab has no or negligible influence on the ability to drive and use machines.

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia in adults

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 either withrituximab monotherapy (as induction treatment or maintenance treatment following induction treatment) orin combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab were IRRswhich occurred 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 frequent reported or observed serious adverse drug 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 ADRs reported include hepatitis B reactivation and PML (see section 4.4.)

The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy aresummarised 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 < 1/1000), very rare (< 1/10,000) andnot known (cannot be estimated from the available data). Within each frequency grouping,undesirable effects are presented in order of decreasing seriousness.

The ADRs identified only during post-marketing surveillance, and for which a frequency could not beestimated, are listed under “not known”.

Table 3 ADRs 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

Verysystem organ Common Uncommon Rare Very rare Not knowncommonclass

Infections and bacterial sepsis, serious viral PML enteroviralinfestations infections, +pneumonia, infection2, meningoencephviral infections, +febrile pneumocystis alitis2, 3+bronchitis infection, jirovecii+herpes zoster,+respiratory tractinfection, fungalinfections,infections ofunknownaetiology, +acutebronchitis,+sinusitis,hepatitis B1

Blood and neutropenia, anaemia, coagulation transient latelymphatic leucopenia, +pancytopenia, disorders, increase in neutropenia4system +febrile +granulocytopeni aplastic serum IgMdisorders neutropenia, a anaemia, levels4+thrombocyto haemolyticpenia anaemia,lymphadenopathy

Immune infusion-related hypersensitivity anaphylaxis tumour lysis infusion-relatedsystem reactions5, syndrome, acute reversibledisorders angioedema cytokine thrombocytoperelease nia5syndrome5,serum sickness

Metabolism hyperglycaemia,and nutrition weight decrease,disorders peripheraloedema, faceoedema,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 severe visiondisorder, loss6conjunctivitis

Ear and tinnitus, ear pain hearing loss6labyrinthdisorders

Cardiac +myocardial +left severe cardiac heart failure5, 7disorders Infarction5,7 , ventricular disorders5, 7arrhythmia, failure,+atrial +supraventri-fibrillation, culartachycardia, tachycardia,+cardiac disorder +ventriculartachycardia,+angina,+myocardialischaemia,bradycardia

Vascular hypertension, vasculitisdisorders orthostatic (predominatelyhypotension, cutaneous),hypotension leukocytoclastic vasculitis

Respiratory, Bronchospasm5, asthma, interstitial lung respiratory lung infiltrationthoracic and respiratory bronchiolitis disease8 failure5mediastinal disease, chest obliterans,disorders pain, dyspnoea, lung disorder,increased cough, hypoxiarhinitis

Gastrointestin nausea vomiting, abdominal gastro-intestinaal disorders diarrhoea, enlargement l perforation8abdominal pain,dysphagia,stomatitis,constipation,dyspepsia,anorexia, throatirritation

Skin and pruritus, urticaria, severe bulloussubcutaneous rash, sweating, night skin reactions,tissue +alopecia sweats, +skin Stevens-disorders disorder Johnsonsyndrome,toxicepidermalnecrolysis(Lyell’ssyndrome)8

Musculoskelet hypertonia,al, connective myalgia,tissue arthralgia, backdisorders pain, neck pain,pain

Renal and renal failure5urinarydisorders

General fever, chills, tumour pain, infusion sitedisorders and asthenia, flushing, painadministratio headache malaise,n site cold syndrome,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 terms marked with '+'where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria) reactions. Only the highestfrequency observed in the trials is reportedincludes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLLsee also section infection belowobserved during post-marketing surveillancesee also section haematologic adverse reactions belowsee also section infusion-related reactions below. Rarely fatal cases reportedsigns and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of rituximabtherapyobserved mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated withinfusion-related reactions8 includes fatal cases

The following terms have been reported as adverse events 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 somecases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversiblethrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris orcongestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrialfibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine releasesyndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. Theincidence 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, includinggrade 3 or 4 infections, were observed during rituximab maintenance treatment up to 2 years whencompared to observation. There was no cumulative toxicity in terms of infections reported over a2-year treatment period. In addition, other serious viral infections either new, reactivated orexacerbated, some of which were fatal, have been reported with rituximab treatment. The majorityof patients had received rituximab in combination with chemotherapy or as part of a haematopoeticstem cell transplant. Examples of these serious viral infections are infections caused by the herpesviruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus(progressive multifocal leukoencephalopathy (PML)), enterovirus (meningoencephalitis) andhepatitis C virus (see section 4.4.). Cases of fatal PML that occurred after disease progression andretreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have beenreported, the majority of which were in patients receiving rituximab in combination with cytotoxicchemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis Binfection (reactivation and primary infection) was 2% in R-FC vs. 0% FC. Progression of Kaposi’ssarcoma has been observed in rituximab-exposed patients with pre-existing Kaposi’s sarcoma.

These cases occurred in non-approved indications and the majority of patients were HIV positive.

In clinical trials with rituximab monotherapy given for 4 weeks, haematological abnormalities occurredin a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia wasreported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During rituximabmaintenance 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. The incidence ofthrombocytopenia was low (<1%, grade 3/4) and was not different between treatment arms. During thetreatment 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-CVP 24% vs. CVP 14%; R-CHOP97% 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 with higher frequencies when compared tochemotherapy alone. However, the higher incidence of neutropenia in patients treated with rituximab andchemotherapy was not associated with a higher incidence of infections and infestations compared topatients treated with chemotherapy alone. Studies in previously untreated and relapsed/refractory CLLhave established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined asneutrophil count remaining below 1x109/L between day 24 and 42 after the last dose) or occurred with alate onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with noprevious prolonged neutropenia or who recovered prior to day 42) following treatment with rituximabplus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropeniaoccurring more than four weeks after the last infusion of rituximab were reported. In the CLL first-linestudy, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm(R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reportedin 11% of patients 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 of grade 3 or4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusionwere reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparablebetween patients treated with rituximab and observation. Cardiac events were reported as serious adverseevents (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischaemia)in 3% of patients treated with rituximab compared to < 1% on observation. In studies evaluating rituximabin combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantlysupraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOPgroup (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%). All of these arrhythmiaseither occurred in the context of a rituximab infusion or were associated with predisposing conditions suchas fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. Nodifference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease. In

CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC,3% FC) and in 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 eight cycles),four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboemboliccerebrovascular accidents during the first treatment cycle. There was no difference between the treatmentgroups in the incidence of other thromboembolic events. In contrast, three patients (1.5%) hadcerebrovascular events in the CHOP group, all of which occurred during the follow-up period. In CLL, theoverall incidence of grade 3 or 4 nervous system disorders was low both in 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 recognised riskfactors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressivetherapy and/or chemotherapy.

Gastrointestinal perforation in some cases leading to death has been observed in patients receivingrituximab for treatment of non-Hodgkin’s lymphoma. In the majority of these cases, rituximab wasadministered with chemotherapy.

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 group throughoutthe 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 observed inpaediatric patients treated with rituximab, in some cases severe and requiring long-term immunoglobulinsubstitution therapy. The consequences of long term B cell depletion in paediatric patients are unknown.

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

Patient subpopulations - rituximab monotherapy

The incidence of ADRs of all grades and grade 3/4 ADR was similar in elderly patients compared toyounger patients (< 65 years).

There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients withoutbulky disease (25.6% vs. 15.4%). The incidence of ADRs of any grade was similar in these two groups.

The percentage of patients reporting ADRs upon re-treatment with further courses of rituximab wassimilar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4

ADRs).

Patient subpopulations - rituximab combination therapy

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

A multicenter, open-label randomized study of Lymphome Malin B chemotherapy (LMB) with or withoutrituximab was conducted in paediatric patients (aged ≥ 6 months to < 18 years old) with previouslyuntreated advanced stage CD20 positive DLBCL/BL/BAL/BLL.

A total of 309 paediatric patients received rituximab and were included in the safety analysis population.

Paediatric patients randomized to the LMB chemotherapy arm with rituximab, or enrolled in the single armpart of the study, were administered rituximab at a dose of 375mg/m2 BSA and received a total of sixintravenous infusions of rituximab (two during each of the two induction courses and one during each ofthe two consolidation courses of the LMB scheme).

The safety profile of rituximab in paediatric patients (aged ≥ 6 months to < 18 years old) with previouslyuntreated advanced stage CD20 positive DLBCL/BL/BAL/BLL was generally consistent in type, natureand severity with the known safety profile in adult NHL and CLL patients. Addition of rituximab tochemotherapy 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 expected adversereaction 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 infusion of100 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 frequency grouping, undesirableeffects are presented in order of decreasing seriousness.

The most frequent adverse reactions considered due to receipt of rituximab were 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 drug reactions reported in clinical trials or duringpost-marketing surveillance occurring in patients with rheumatoid arthritisreceiving rituximab

MedDRA

Verysystem organ Common Uncommon Rare Very rare Not knowncommonclass

Infections and upper bronchitis, PML, Serious viralinfestations respiratory sinusitis, reactivation infection 1 ,tract infection, gastroenteritis, of enteroviralurinary tract tinea pedís hepatitis B meningoencepinfections halitis2

Blood and Neutropenia3 late serumlymphatic neutropenia4 sickness-likesystem reactiondisorders

Immune system 5infusion-related 5infusion-relatdisorders reactions ed reactions

General (hypertension, (generaliseddisorders and nausea, rash, oedema,administration pyrexia, bronchospasmsite conditions pruritus, , wheezing,urticaria, throat laryngealirritation, hot oedema,flush, angioneurotichypotension, oedema,rhinitis, rigors, generalisedtachycardia, pruritis,fatigue, anaphylaxis,oropharyngeal anaphylactoidpain, peripheral reaction)oedema,erythema)

Metabolism hypercholesteroleand nutritional miadisorders

Psychiatric depression,disorders anxiety

Nervous system headache paraesthesia,

MedDRA

Verysystem organ Common Uncommon Rare Very rare Not knowncommonclassdisorders migraine,dizziness, sciatica

Cardiac angina atrial flutterdisorders pectoris,atrialfibrillation,heart failure,myocardialinfarction

Gastrointestinal dyspepsia,disorders diarrhoea, gastro-oesophagealreflux, mouthulceration, upperabdominal pain

Skin and alopecia toxicsubcutaneous epidermaltissue disorders necrolysis(Lyell’ssyndrome),

Stevens-

Johnsonsyndrome7

Musculo- arthralgia /skeletal musculoskeletaldisorders pain,osteoarthritis,bursitis

Investigations decreased IgM decreased IgG6 6levels levels1 See also section infections below2 Observed during post-marketing surveillance3 Frequency category derived from laboratory values collected as part of routine laboratory monitoring inclinical trials4 Frequency category derived from post-marketing data.5 Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRsmay occur as 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 ADR profile to that observed following firstexposure. The rate of all ADRs following first rituximab exposure was highest during the first 6 monthsand declined thereafter. This is mostly accounted for by IRRs (most frequent during the first treatmentcourse), RA exacerbation and infections all of which were more frequent in the first 6 months oftreatment.

The most frequent ADRs following receipt of rituximab in clinical studies were IRRs (refer to Table 4).

Among the 3189 patients treated with rituximab, 1,135 (36%) experienced at least one IRR with733/3,189 (23%) of patients experiencing an IRR following first infusion of the first exposure torituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1%(17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to

IRRs in the clinical trials. The proportion of CTC Grade 3 events, and of IRRs leading to withdrawaldecreased by course and were rare from course 3 onwards. Premedication with intravenousglucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Severe

IRRs with fatal outcome have been reported in the post-marketing setting.

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 mostly ofupper 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 of seriousinfections did not show any significant increase following multiple courses of rituximab. Lowerrespiratory tract infections (including pneumonia) have been reported during clinical trials, at a similarincidence in the rituximab-arms compared to control arms.

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

Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported followinguse of rituximab for the treatment of autoimmune diseases. This includes rheumatoid arthritis and off-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 rheumatoid arthritis patientsreceiving rituximab (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 posterior leukoencephalopathysyndrome (RPLS) have been reported. Signs and symptoms included visual disturbance, headache, seizuresand altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requiresconfirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, includingthe patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

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

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and 0.27%(2/731) of placebo-treated patients developed severe neutropenia.

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported inthe 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 infections afterthe development of low IgG or IgM (see section 4.4).

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

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

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

The ADRs listed in Table 5 were all adverse events which occurred at an incidence of ≥ 5% in therituximab group and at a higher frequency than the comparator group.

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

MedDRA system organ class

Adverse reactions Frequency

Urinary tract infection 7%

Bronchitis 5%

Herpes zoster 5%

Nasopharyngitis 5%

Serious viral infection 1, 2 Not known

Enteroviral meningoencephalitis 1 Not known

Blood and lymphaticsystem disorders

Thrombocytopenia 7%

Cytokine release syndrome 5%

Hyperkalaemia 5%

Insomnia 14%

Dizziness 10%

Tremor 10%

Hypertension 12%

Flushing 5%

Respiratory, thoracic andmediastinal disorders

Cough 12%

Dyspnoea 11%

Epistaxis 11%

Nasal congestion 6%

Gastrointestinaldisorders

Diarrhoea 18%

MedDRA system organ class

Adverse reactions Frequency

Dyspepsia 6%

Constipation 5%

Skin and subcutaneoustissue disorders

Acne 7%

Musculoskeletal and connectivetissue disorders

Muscle spasms 18%

Arthralgia 15%

Back pain 10%

Muscle weakness 5%

Musculoskeletal pain 5%

Pain in extremities 5%

General disorders andadministration site conditions

Peripheral oedema 16%

Decreased haemoglobin 6%1 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 postmarketing surveillance.

MedDRA system organ class

Frequency

Adverse reaction

Bronchitis 14%

Rhinitis 5%

Serious viral infection1, 2 Not known

Enteroviral meningoencephalitis 1 Not known

General disorders and administration siteconditions

Pyrexia 9%

Influenza-like illness 5%

Oedema peripheral 5%

Diarrhoea 7%

Dyspnoea 9%

Infusion-related reactions3 12%1 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 drug reactions section.

The overall safety profile was consistent with the well-established safety profile for rituximab in approvedautoimmune indications, including GPA and MPA. Overall, 4% of patients in the rituximab armexperienced adverse events leading to discontinuation. Most adverse events in the rituximab arm were mildor moderate in intensity. No patients in the rituximab arm had fatal adverse events.

The most commonly reported events considered as ADRs were infusion-related reactions and infections.

In a long-term observational safety study, 97 GPA and MPA patients received treatment with rituximab(mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician’s standard practice anddiscretion. The overall safety profile was consistent with the well-established safety profile of rituximab in

RA and GPA/MPA and no new adverse drug 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-monthfollow-up, up to 4.5 years overall. During the follow-up phase, rituximab was given at the discretion of theinvestigator (17 out of 25 patients received additional rituximab treatment). Concomitant treatment withother immunosuppressive therapy was permitted (see section 5.1).

ADRs were considered as adverse events that occurred at an incidence of ≥ 10%. These included:

infections (17 patients [68%] in the remission induction phase; 23 patients [92%] in the overall studyperiod), IRRs (15 patients [60%] in the remission induction phase; 17 patients [68%] in the overall studyperiod), and nausea (4 patients [16%] in the remission induction phase; 5 patients [20%] in the overallstudy period).

During the overall study period, the safety profile of rituximab was consistent with that reported during theremission 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, includingadult 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 intravenous glucocorticoidswhich may reduce the incidence and severity of these events.

In GPA/MPA Study 2 (adult maintenance study), 7/57 (12%) patients in the rituximab arm experiencedat least one infusion-related reaction. The incidence of IRR symptoms was highest during or after thefirst infusion (9%) and decreased with subsequent infusions (< 4%).

In the clinical trial in paediatric patients with GPA or MPA, the reported IRRs were predominantly seen withthe first infusion (8 patients [32%]), and then decreased over time with the number of rituximab infusions(20% with the second infusion, 12% with the third infusion and 8% with the fourth infusion). The mostcommon IRR symptoms reported during the remission induction phase were: headache, rash, rhinorrhea andpyrexia (8%, for each symptom). The observed symptoms of IRRs were similar to those known in adult

GPA or MPA patients treated with rituximab. The majority of IRRs were Grade 1 and Grade 2, there weretwo non-serious Grade 3 IRRs, and no Grade 4 or 5 IRRs reported. One serious Grade 2 IRR (generalizedoedema which resolved with treatment) was reported 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% CI197-285) at the 6-month primary endpoint. Infections were predominately mild to moderate andconsisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections. The rateof serious infections was approximately 25 per 100 patient years. The most frequently reported seriousinfection 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. The incidenceof all grade infections was similar between the arms. Infections were predominately mild to moderate.

The most common infections in the rituximab arm included upper respiratory tract infections,gastroenteritis, urinary tract infections and herpes zoster. The incidence of serious infections was similarin both arms (approximately 12%). The most commonly reported serious infection in the rituximab groupwas mild or moderate bronchitis.

In the clinical trial in paediatric patients with severe, active GPA and MPA, 91% of reported infections werenon-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 tract infections (16%),sinusitis (16%), viral URTIs (16%), ear infection (12%), gastroenteritis (12%), pharyngitis (12%), urinarytract infection (12%). Serious infections were reported in 7 patients (28%), and included: influenza (2patients [8%]) and lower respiratory tract infection (2 patients [8%]) as the most frequently reported events.

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

In GPA/MPA Study 1, the incidence of malignancy in rituximab treated patients in the GPA and MPAclinical trial was 2.00 per 100 patient years at the study common closing date (when the final patient hadcompleted 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-associated vasculitis.

In the paediatric clinical trial, no malignancies were reported with a follow-up period of up to 54 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 was 2.1 per 100 patientyears (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 posterior leukoencephalopathysyndrome (RPLS) have been reported in autoimmune conditions. 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 recognised riskfactors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressivetherapy and/or chemotherapy.

A small number of cases of hepatitis B reactivation, some with fatal outcome, have been reported ingranulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab in the post-marketing setting.

Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in adultand 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 with normalimmunoglobulin levels at baseline had low IgA, IgG and IgM levels, respectively, compared to 25%,50% and 46% in the cyclophosphamide group. The rate of overall infections and serious infections wasnot increased after the development of low IgA, IgG or IgM.

In GPA/MPA Study 2, no clinically meaningful differences between the two treatment arms or decreasesin 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). Threepatients received treatment with intravenous immunoglobulin (IV-IG). Based on limited data, no firmconclusions can be drawn regarding whether prolonged low IgG and IgM led to an increased risk of seriousinfection in these patients. The consequences of long term B cell depletion in paediatric patients areunknown.

In GPA/MPA Study 1, 24% of patients in the rituximab group (single course) and 23% of patients in thecyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not associatedwith 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 vs.

5% for azathioprine treated patients.

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

The safety profile of rituximab in combination with short-term, low-dose glucocorticoids in the treatmentof patients with pemphigus vulgaris was studied in a Phase 3, randomised, controlled, multicenter, open-label study in pemphigus patients that included 38 pemphigus vulgaris (PV) patients randomised to therituximab group (PV Study 1). Patients randomised to the rituximab group received an initial 1000 mgintravenous on Study Day 1 and a second 1000 mg intravenous on Study Day 15. Maintenance doses of500 mg intravenous were administered at months 12 and 18. Patients could receive 1000 mg intravenousat the time of relapse (see section 5.1).

In PV Study 2, a randomized, double-blind, double-dummy, active-comparator, multicenter studyevaluating the efficacy and safety of rituximab compared with mycophenolate mofetil (MMF) in patientswith moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment withrituximab (initial 1000 mg intravenous on Study Day 1 and a second 1000 mg intravenous on Study Day 15repeated 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 other approvedautoimmune indications.

Adverse reactions from PV Studies 1 and 2 are presented in Table 7. In PV Study 1, ADRs were defined asadverse events which 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 group up tomonth 24. No patients were withdrawn due to ADRs in Study 1. In PV Study 2, ADRs were defined asadverse events occurring in ≥5% of patients in the rituximab arm and assessed as related.

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

MedDRA system organ class Very common Common Not Known

Infections and infestations Upper respiratory Herpes virus infection Serious viraltract infection Herpes zoster infection 1, 2

Oral herpes Enteroviral

Conjunctivitis meningoencephalitis

Nasopharyngitis 1

Oral candidiasis

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

Psychiatric disorders Persistent depressive Major depressiondisorder Irritability

Nervous system disorders Headache Dizziness

Cardiac disorders Tachycardia

Gastrointestinal disorders Abdominal pain upper

Skin and subcutaneous Alopecia Pruritustissue disorders Urticaria

Skin disorder

Musculoskeletal , connective Musculoskeletal paintissue and bone 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 aftereach infusion, and adverse events occurring on the day of or one day after the infusion. The mostcommon infusion-related reaction symptoms/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 reactions weremild to moderate. The proportion of patients experiencing an infusion-related reaction was 29% (11patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, andfourth infusions, respectively. No patients were withdrawn from treatment due to infusion-relatedreactions. Symptoms of infusion-related reactions were similar in type and severity to those seen in RAand 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, andfourth infusions, respectively. In 11/15 patients who experienced at least one IRR, the IRRs were Grade 1or 2. In 4/15 patients, Grade ≥3 IRRs were reported and led to discontinuation of rituximab treatment;three of the four patients experienced serious (life-threatening) IRRs. Serious IRRs occurred at the first(2 patients) or second (1 patient) infusion and resolved with symptomatic treatment.

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 in therituximab group were herpes simplex and zoster infections, bronchitis, urinary tract infection, fungalinfection and conjunctivitis. Three patients (8%) in the rituximab group experienced a total of 5 seriousinfections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, lung infection,

Staphylococcal sepsis) and one patient (3%) in the standard-dose prednisone group experienced a seriousinfection (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, oral candidiasisand urinary tract infection. Six patients (9%) in the rituximab arm experienced serious infections.

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

PV Study 2, in the rituximab arm, transient decreases in lymphocyte count, driven by decreases in theperipheral T-cell populations, as well as a transient decrease in phosphorus level were very commonlyobserved post-infusion. These were considered to be induced by intravenous 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 the developmentof low IgG or IgM.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed 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 5000 mg (2250 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 a doseof 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01FA01.

Truxima 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-glycosylated phosphoprotein,located on pre-B and mature B lymphocytes. The antigen is expressed on > 95% of all B cellnon-Hodgkin’s lymphomas.

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

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruitimmune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysisinclude complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependentcellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the surface ofgranulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on B lymphocytes has alsobeen 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 treatment andgenerally returned to normal levels within 12 months after completion of therapy, although in somepatients this may take longer (up to a median recovery time of 23 months post-induction therapy). Inrheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observedfollowing two infusions of 1000 mg rituximab separated by a 14-day interval. Peripheral blood B cellcounts begin to increase from week 24 and evidence for repopulation is observed in the majority ofpatients by week 40, whether rituximab was administered as monotherapy or in combination withmethotrexate. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years ormore after their last dose of rituximab. In patients with GPA or MPA, the number of peripheral blood Bcells decreased to < 10 cells/μL after two weekly infusions of rituximab 375 mg/m2, and remained at thatlevel in most patients up to the 6 month time point. The majority of patients (81%) showed signs of B cellreturn, with counts > 10 cells/μL by month 12, increasing to 87% of patients by month 18.

Clinical experience in non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia

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 to progression(TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was higher in patientswith IWF B, C, and D histological subtypes as compared to IWF A subtype (58% vs. 12%), higher inpatients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53% vs. 38%), and higher inpatients with chemosensitive relapse as compared to chemoresistant (defined as duration of response < 3months) relapse (50% vs. 22%). ORR in patients previously treated with autologous bone marrowtransplant (ABMT) was 78% versus 43% in patients with no ABMT. Neither age, sex, lymphoma grade,initial diagnosis, presence nor absence of bulky disease, normal or high LDH nor presence of extranodaldisease had a statistically significant effect (Fisher’s exact test) on response to rituximab. A statisticallysignificant correlation was noted between response rates and bone marrow involvement. 40% of patientswith bone marrow involvement responded compared to 59% of patients with no bone marrowinvolvement (p=0.0186). This finding was not supported by a stepwise logistic regression analysis inwhich the following factors were identified as prognostic factors: histological type, bcl-2 positivity atbaseline, resistance to last chemotherapy and bulky disease.

In a multicentre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular Bcell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for eight doses. The ORR was57% (95% Confidence interval (CI); 41% - 73%; CR 14%, PR 43%) with a projected median TTP forresponding 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 (single lesion≥ 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m2 of rituximab as intravenousinfusion 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 multicentre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular Bcell NHL, who had achieved an objective clinical response to a prior course of rituximab, were re-treatedwith 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. Three of the patients hadreceived two courses of rituximab before enrolment and thus were given a third course in the study. Twopatients were re-treated twice in the study. For the 60 re-treatments on study, the ORR was 38% (CI95%26% - 51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months(range 5.4 - 26.6). This compares favourably with the TTP achieved after the prior course 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 was 53months. 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 and was13.5 months in the CVP group (p < 0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significant clinicaldifference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were 80.9% forpatients 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 improvements inresponse rates, time-dependent parameters as well as in overall survival. Key results from all four studiesare 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 follicularlymphoma

Median Median

Treatment, OS rates,

Study FU, ORR, % CR,% TTF/PFS/ EFS,

N %months months

Median TTP: 53-months

CVP, 159 57 10 14.7 71.1

M39021 53

R-CVP, 162 81 41 33.6 80.9

P<0.0001 p=0.029

CHOP, 205 90 17 Median TTF: 2.6 18-months

GLSG’00 18

R-CHOP, 96 20 years 90

Median Median

Treatment, OS rates,

Study FU, ORR, % CR,% TTF/PFS/ EFS,

N %months months223 Not reached 95p < 0.001 p = 0.016

Median PFS: 48-months 74

MCP, 96 75 25

OSHO‐39 47 28.8 Not reached 87

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

CHVP-IFN,

Median EFS: 36 42-months 84183 85 49

FL2000 42 Not reached 91

R-CHVP- 94 76p < 0.0001 p = 0.029

IFN, 175

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, multicentre, phase III trial 1193 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 1078 patients responded toinduction therapy, of which 1018 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 secondary endpointsevent-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next chemotherapy(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 months) (median FU: 9.0 years)

Observation Rituximab Observation Rituximab

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

Primary efficacy

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

Secondary efficacy

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

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 <0.0001hazard 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% 67%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.

CI: confidence interval; FU: follow-up; OS: overall survival; TNLT: time to next anti-lymphoma treatment; TNCT:

time to next chemotherapy treatment; NR: not reached at time of clinical cut-off.

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 pronounced effect in elderlypatients (> 70 years of age), however sample sizes were small.

In a prospective, open label, international, multicentre, phase III trial, 465 patients withrelapsed/refractory follicular lymphoma were randomised in a first step to induction therapy with either

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 the trend testof 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 was 28months from maintenance randomisation. Maintenance treatment with rituximab led to a clinicallyrelevant and statistically significant improvement in the primary endpoint, PFS, (time from maintenancerandomisation to relapse, disease progression or death) when compared to observation alone (p< 0.0001log-rank test). The median PFS was 42.2 months in the rituximab maintenance arm compared to 14.3months in the observation arm. Using a cox regression analysis, the risk of experiencing progressivedisease or death was reduced by 61% with rituximab maintenance treatment when compared toobservation (95% CI; 45%-72%). Kaplan-Meier estimated progression-free rates at 12 months were 78%in the rituximab maintenance group vs. 57% in the observation group. An analysis of overall survivalconfirmed the significant benefit of rituximab maintenance over observation (p=0.0039 log-rank test).

Rituximab maintenance treatment reduced the risk of death by 56% (95% CI; 22%-75%).

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

Kaplan-Meier estimate ofmedian time to event (months) Risk

Efficacy parameter

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

Progression‐free survival14.3 42.2 < 0.0001 61%(PFS)

Overall survival NR NR 0.0039 56%

Time to new lymphoma20.1 38.8 < 0.0001 50%treatment

Disease‐free survivala 16.5 53.7 0.0003 67%

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, regardless ofinduction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (Table11). Rituximab maintenance treatment significantly prolonged median PFS in patients responding to

CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p< 0.0001) as well as in thoseresponding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). Althoughsubgroups were small, rituximab maintenance treatment provided a significant benefit in terms of overallsurvival for both patients responding to CHOP and patients responding to R-CHOP, although longerfollow-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 750mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, andprednisolone 40 mg/m2/day on days 1-5) every 3 weeks for eight cycles, or rituximab 375 mg/m2 plus

CHOP (R-CHOP). Rituximab was administered on the first day of the treatment cycle.

The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a medianfollow-up duration of approximately 31 months. The two treatment groups were well balanced in baselinedisease characteristics and disease status. The final analysis confirmed that R-CHOP treatment wasassociated with a clinically relevant and statistically significant improvement in the duration of event-freesurvival (the primary efficacy parameter; where events were death, relapse or progression of lymphoma, orinstitution of a new anti-lymphoma treatment) (p=0.0001). Kaplan Meier estimates of the median durationof event-free survival were 35 months in the R-CHOP arm compared to 13 months in the CHOP arm,representing a risk reduction of 41%. At 24 months, estimates for overall survival were 68.2% in the R-

CHOP arm compared to 57.4% in the CHOP arm. A subsequent analysis of the duration of overallsurvival, carried out with a median follow-up duration of 60 months, confirmed the benefit of R-CHOPover CHOP treatment (p=0.0071), representing a risk reduction of 32%.

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

IPI.

Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of 356patients evaluated for anti-drug antibody (ADA), 1.1% (4 patients) were positive.

Chronic lymphocytic leukaemia

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 dosage of 375 mg/m2 during the first cycle one day prior tochemotherapy and at a dosage 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 with monoclonalantibodies or if they were refractory (defined as failure to achieve a partial remission for at least 6months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for thefirst-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 months inthe 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-ranktest) (Table 12a). The benefit in terms of PFS was consistently observed in most patient subgroupsanalysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 12b).

Table 12a First-line treatment of chronic lymphocytic leukaemiaoverview of efficacy results for rituximab plus FC vs. FC alone - 48.1 monthsmedian observation time

Efficacy parameter Kaplan-Meier estimate of median time to Riskevent (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 chronic lymphocytic leukaemiahazard ratios of progression-free survival according to binet stage (ITT) - 48.1months median observation time

Number ofp-value (Waldpatients Hazard ratiotest, not

Progression‐free survival (PFS) (95% CI)

FC R‐FC adjusted)

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) was 30.6 monthsin the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). The benefit in terms of PFSwas observed in almost all patient subgroups analysed according to disease risk at baseline. A slight butnot significant improvement in overall survival was reported in the R-FC compared to the FC arm.

Table 13 Treatment of relapsed/refractory chronic lymphocytic leukaemia - overview ofefficacy results for rituximab plus FC vs. FC alone (25.3 months medianobservation 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. NR: not reached; N/A: not applicable

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

**: 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 multicenter, open-label, randomized 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 in combination with rituximab wasconducted in paediatric patients with previously untreated advanced stage 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. Patientswere randomized to receive either LMB chemotherapy or six intravenous infusions of rituximab at a doseof 375 mg/m2 BSA in combination with LMB chemotherapy (two during each of the two induction coursesand one during each of the two consolidation courses) as per the LMB scheme. A total of 328 randomizedpatients were included in the efficacy analyses, of which one patient under 3 years of age receivedrituximab in combination with LMB chemotherapy.

The two treatment arms, LMB (LMB chemotherapy) and R-LMB (LMB chemotherapy with rituximab),were well balanced with regards to baseline characteristics. Patients had a median age of 7 and 8 years inthe 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 Murphy staging, 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 the patients (45.1% in both arms) had bonemarrow involvement, and most patients (72.6% in the LMB arm 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 ofprogressive disease, relapse, second malignancy, death from any cause, or non-response as evidenced bydetection of viable cells in residue after the second CYVE course, whichever occurs first. The secondaryefficacy endpoints were OS and CR (complete remission).

At the pre-specified interim analysis with approximately 1 year of median follow-up, clinically relevantimprovement in the primary endpoint of EFS was observed, with 1-year rate estimates of 94.2% (95% CI,88.5% - 97.2%) in the R-LMB arm vs. 81.5% (95% CI, 73.0% - 87.8%) in the LMB arm, and adjusted Cox

HR 0.33 (95% CI, 0.14 - 0.79). Upon IDMC (independent data monitoring committee) recommendationbased on this result, the randomization was halted and patients in the LMB arm were allowed to cross overto receive rituximab.

Primary efficacy analyses were performed in 328 randomized patients with a median follow-up of 3.1years. The results are described in Table 14.

Table 14: Overview of primary efficacy results (ITT population)

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

LMB chemotherapy alone, with an EFS HR 0.32 (90% CI 0.17 - 0.58) from a Cox regression analysisadjusting for national group, histology, and therapeutic group. While no major differences in numbers ofpatients achieving CR was observed between the two treatment groups, the benefit of rituximab 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 chronic lymphocyticleukaemia, and in the paediatric population from birth to < 6 months of age in CD20 positive diffuselarge B-cell lymphoma. See section 4.2 for information on paediatric use.

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 or more

TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to thecriteria of the American College of Rheumatology (ACR). Rituximab was administered as twointravenous infusions separated by an interval of 15 days. Patients received 2 x 1000 mg intravenousinfusions of rituximab or placebo in combination with MTX. All patients received concomitant 60 mg oralprednisone on days 2-7 and 30 mg on days 8-14 following the first infusion. The primary endpoint wasthe proportion of patients who achieved an ACR20 response at week 24. Patients were followed beyondweek 24 for long-term endpoints, including radiographic assessment at 56 weeks and at 104 weeks.

During this time, 81% of patients, from the original placebo group received rituximab between weeks 24and 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) havemet their primary endpoints. Rituximab is not indicated for these patients, since the safety data aboutlong-term rituximab treatment are insufficient, in particular concerning the risk of development ofmalignancies and PML.

Rituximab in combination with methotrexate significantly increased the proportion of patients achievingat least a 20% improvement in ACR score compared with patients treated with methotrexate alone (Table15). Across all development studies the treatment benefit was similar in patients independent 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, disability indexscores (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 1000 mg)

Trial 1 N= 201 N= 298

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

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

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

EULAR Response44 (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 time point: ***p ≤ 0.0001

Patients treated with rituximab in combination with methotrexate had a significantly greater reduction indisease activity score (DAS28) than patients treated with methotrexate alone (Table 15). Similarly, a goodto moderate European League Against Rheumatism (EULAR) response was achieved by significantlymore rituximab treated patients treated with rituximab and methotrexate compared to patients treated withmethotrexate 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 between weeks16-24 or in the extension trial, before week 56. A higher proportion of patients receiving the originalrituximab/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 × 1000 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 by oneyear

* p <0.05, ** p < 0.001. Abbreviation: NS: non significant

Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis at 2years in Trial 1 demonstrated significantly reduced progression of structural joint damage in patientsreceiving rituximab in combination with methotrexate compared to methotrexate alone as well as asignificantly higher proportion of patients with no progression of joint damage over the 2-year period.

Significant reductions in disability index (HAQ-DI) and fatigue (FACIT-Fatigue) scores were observed inpatients treated with rituximab compared to patients treated with methotrexate alone. The proportions ofrituximab treated patients showing a minimal clinically important difference (MCID) in HAQ-DI (definedas an individual total score decrease of >0.22) was also higher than among patients receiving methotrexatealone (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,a 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† Rituximab+MTX

Placebo+MTX(2 x 1000 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 ***

- 9.1n=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-ESR ‐1.97** ‐1.50 ‐2.48*** ‐1.72

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 in sustainedimprovements in the clinical signs and symptoms of RA, as indicated by ACR, DAS28-ESR and EULARresponses which was evident in all patient populations studied (Figure 2). Sustained improvement inphysical function as indicated by the HAQ-DI score and the proportion of patients achieving MCID for

HAQ-DI were observed.

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

A total of 392/3095 (12.7%) patients with rheumatoid arthritis tested positive for ADA in clinical trialsfollowing therapy with rituximab. The emergence of ADA was not associated with clinical deteriorationor 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 the second infusion ofsubsequent courses.

The European Medicines Agency has waived the obligation to submit the results of studies with rituximabin all subsets of the paediatric population with autoimmune arthritis. See section 4.2 for information onpaediatric use.

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) for3-6 months or rituximab (375 mg/m2) once weekly for 4 weeks. All patients in the cyclophosphamidearm received azathioprine maintenance therapy during follow-up. Patients in both arms received 1000 mgof pulse intravenous (IV) methylprednisolone (or another equivalent-dose glucocorticoid) per day for 1 to3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day). Prednisone tapering was tobe completed by 6 months from the start of study 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 pre-specified non-inferiority margin for the treatment difference was 20%.

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

Treatment difference

Rituximab Cyclophosphamide(Rituximab -(n = 99) (n = 98)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-determinednon-inferiority margin (− 20%).b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.

Table 20 Complete remission at 6-months by disease status

Rituximab Cyclophosphamide Difference (CI 95%)

All patients newly n=99 n=98diagnosed n=48 n=48relapsing 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 CR at18 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 at 18months. From month 12 to month 18, 8 relapses were observed in the rituximab group compared withfour in the cyclophosphamide group.

A total of 23/99 (23%) rituximab-treated patients from the induction of remission trial tested positive for

ADA by 18 months. None of the 99 rituximab-treated patients were ADA positive at screening. There wasno apparent trend or negative impact of the presence of ADA on safety or efficacy in the induction of theremission trial.

A total of 117 patients (88 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associated vasculitis)in disease remission were randomised to receive azathioprine (59 patients) or rituximab (58 patients) in aprospective, multi-center, controlled, open-label study. Included patients were 21 to 75 years of age and hadnewly diagnosed or relapsing disease in complete remission after combined treatment with glucocorticoidsand pulse cyclophosphamide. The majority of patients were ANCA-positive at diagnosis or during the courseof their disease; had histologically confirmed necrotizing small-vessel vasculitis with a clinical phenotype of

GPA or MPA, or renal limited ANCA-associated vasculitis; or both.

Remission-induction therapy included intravenous prednisone, administered as per the investigator’sdiscretion, preceded in some patients by methylprednisolone pulses, and pulse cyclophosphamide untilremission was 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 intravenous every6 months for 18 months) or azathioprine (administered orally at a dose of 2 mg/kg/day for 12 months, then1.5 mg/kg/day for 6 months, and finally 1 mg/kg/day for 4 months (treatment discontinuation after these 22months)). Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg per day) for atleast 18 months after randomization. Prednisone dose tapering and the decision to stop prednisone treatmentafter month 18 were left at the investigator’s discretion.

All patients were followed until month 28 (10 or 6 months, respectively, after the last rituximab infusion orazathioprine dose). Pneumocystis jirovecii pneumonia prophylaxis was required for all patients with CD4+

T-lymphocyte counts less than 250 per cubic millimeter.

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 of vasculitisactivity ([BVAS] > 0) that could lead to organ failure or damage or could be life threatening) occurred in 3patients (5%) in the rituximab group and 17 patients (29%) in the azathioprine group (p=0.0007). Minorrelapses (not life threatening and not involving major organ damage) occurred in seven patients in therituximab group (12%) and eight patients in the azathioprine group (14%).

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

Figure 3: Cumulative incidence over time of 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 trial developed

ADA. There was no apparent trend or negative impact of the presence of ADA on safety or efficacy in themaintenance therapy clinical trial.

Study WA25615 (PePRS) was a multicenter, open-label, single-arm, uncontrolled study in 25 paediatricpatients (≥ 2 to < 18 years old) with severe, active GPA or MPA. The median age of patients in the studywas: 14 years (range: 6-17 years) and the majority of patients (20/25 [80%]) were female. A total of 19patients (76%) had GPA and 6 patients (24%) had MPA at baseline. Eighteen patients (72%) had newlydiagnosed disease upon study entry (13 patients with GPA and 5 patients with MPA) and 7 patients hadrelapsing 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-monthfollow-up, up to a maximum of 54 months (4.5 years) overall. Patients were to receive a minimum of 3doses of intravenous methylprednisolone (30 mg/kg/day, not exceeding 1 g/day) prior to the first rituximabintravenous infusion. If clinically indicated, additional daily doses (up to three), of intravenousmethylprednisolone 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 6 tomaintain PVAS remission and control disease activity (including progressive disease or flare) or to achievefirst remission.

Percentage of Patients with First

Major Relapse

All 25 patients completed all four once weekly intravenous infusions for the 6-month remission inductionphase. 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 in paediatric

GPA and MPA patients (≥ 2 to < 18 years old). The efficacy objectives of the study were exploratory andprincipally assessed using the Pediatric Vasculitis Activity Score (PVAS) (Table 21).

Cumulative Glucocorticoid dose (intravenous and oral) by Month 6:

Twenty-four out of 25 patients (96%) in Study WA25615 achieved oral glucocorticoid taper to 0.2mg/kg/day (or less than or equal to 10 mg/day, whichever was lower) at or by Month 6 during the protocol-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 Mmonth 18 (median =5 mg [IQR:

1-5]).

During the Overall Study Period, patients received between 4 and 28 infusions of rituximab (up to 4.5 yrs[53.8 months]). Patients received up to 375 mg/m2 x 4 of rituximab, approximately every 6 months at thediscretion of the investigator. In total, 17 out of 25 patients (68%) received additional rituximab treatmentat or post Month 6 until the Common Close Out, 14 out of these 17 patients received additional rituximabtreatment 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) at theassessment time-point.α the efficacy results are exploratory and no formal statistical testing was performed for these endpoints rituximab,treatment (375 mg/m2 x 4 infusions) up to Month 6 was identical for all patients. Follow-up treatment post Month 6was at the discretion of the investigator.

A total of 4/25 patients (16%) developed ADA during the overall study period. Limited data shows therewas 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 with rituximabin paediatric population < 2 years of age in severe, active GPA or MPA. See section 4.2 for information onpaediatric use.

Clinical experience in pemphigus vulgaris

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 pemphigusvulgaris [PV] and 16 pemphigus foliaceus [PF]) in this randomised, open-label, controlled, multicenterstudy. Patients were between 19 and 79 years of age and had not received prior therapies for pemphigus. Inthe PV population, 5 (13%) patients in the rituximab group and 3 (8%) patients in the standard prednisonegroup had moderate disease and 33 (87%) patients in the rituximab group and 33 (92%) patients in thestandard-dose prednisone group had severe disease according to disease severity defined by Harman’scriteria.

Patients were stratified by baseline disease severity (moderate or severe) and randomised 1:1 to receiveeither rituximab and low-dose prednisone or standard-dose prednisone. Patients randomised to therituximab 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 moderate disease or1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease, and a second intravenousinfusion of 1000 mg on Study Day 15. Maintenance infusions of rituximab 500 mg were administered atmonths 12 and 18. Patients randomised to the standard-dose prednisone group received an initial1 mg/kg/day oral prednisone tapered off over 12 months if they had moderate disease or 1.5 mg/kg/day oralprednisone tapered off over 18 months if they had severe disease. Patients in the rituximab group whorelapsed could receive an additional infusion of rituximab 1000 mg in combination with reintroduced orescalated prednisone dose. Maintenance and relapse infusions were administered no sooner than 16 weeksfollowing the previous infusion.

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

The study showed statistically significant results of rituximab and low-dose prednisone over standard-doseprednisone 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 corticosteroid therapyfor two months or more at month 24 (Intent-to-Treat Population - PV)

Rituximab + Prednisone

Prednisone N=36 p-value a 95% CI b

N=38

Number of responders 34 (89.5%) 10 (27.8%) <0.0001 61.7% (38.4, 76.5)(response rate [%])a p-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 minimal therapy(prednisone dose of 10 mg or less per day) compared to standard-dose prednisone patients over 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) therapyover 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 randomized, double-blind, double-dummy, active-comparator, multicenter 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) at studyentry and tapered to reach a dose of 60 or 80 mg/day by Day 1. Patients had a confirmed diagnosis of PVwithin the previous 24 months and evidence of moderate-to-severe disease (defined as a total Pemphigus

Disease Area Index, PDAI, activity score of  15).

One hundred and thirty-five patients were randomized to treatment with rituximab 1000 mg administeredon Day 1, Day 15, Week 24 and Week 26 or oral MMF 2 g/day for 52 weeks in combination with 60 or80 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 of lesionswith no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, andmaintaining this response for at least 16 consecutive weeks, during the 52-week treatment period.

The study demonstrated the superiority of rituximab over MMF in combination with a tapering course oforal corticosteroids in achieving CR off 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% of patients hadestablished disease (duration of illness  6 months and received prior treatment for PV).

Table 23 Percentage of PV Patients Who Achieved Sustained Complete Remission Off

Corticosteroid 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 (response 25 (40.3%) 6 (9.5%) 30.80% (14.70%, 45.15%) <0.0001rate [%])19 (39.6%) 4 (9.1%)

Newly diagnosed patients6 (42.9%) 2 (10.5%)

Patients with established 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 total number ofdisease 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 secondaryendpoints 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 the rituximabgroup 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 compared to

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 onsafety or efficacy in PV Study 2.

Adult Non-Hodgkin’s lymphoma

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 rituximab dosesranged from 100 to 500 mg/m2), the typical population estimates of nonspecific clearance (CL1), specificclearance (CL2) likely contributed by B cells or tumour burden, and central compartment volume ofdistribution (V1) were 0.14 L/day, 0.59 L/day, and 2.7 L, respectively. The estimated median terminalelimination half-life of rituximab was 22 days (range, 6.1 to 52 days). Baseline CD19-positive cell countsand size of measurable tumour lesions contributed to some of the variability in CL2 of rituximab in datafrom 161 patients given 375 mg/m2 as an intravenous infusion for 4 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 lesionsize. V1 varied by body surface area (BSA) and CHOP therapy. This variability in V1 (27.1% and19.0%) contributed by the range in BSA (1.53 to 2.32 m2) and concurrent CHOP therapy, respectively,were relatively small. Age, gender and WHO performance status had no effect on the pharmacokineticsof rituximab. This analysis suggests that dose adjustment of rituximab with any of the tested covariates isnot expected to result in a meaningful reduction in its pharmacokinetic variability.

Rituximab, administered as an intravenous infusion at a dose of 375 mg/m2 at weekly intervals for 4doses to 203 patients with NHL naive to rituximab, yielded a mean Cmax following the fourth infusionof 486 µg/mL (range, 77.5 to 996.6 µg/mL). Rituximab was detectable in the serum of patients 3 - 6months after completion of last treatment.

Upon administration of rituximab at a dose of 375 mg/m2 as an intravenous infusion at weekly intervalsfor 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusion, spanningfrom a mean of 243 µg/mL (range, 16 - 582 µg/mL) after the first infusion to 550 µg/mL (range, 171 -1177 µg/mL) after the eighth infusion.

The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 in combinationwith 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 of 35 patientsaged 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 of the two induction cycles(cycle 1 and 2) followed by one rituximab intravenous infusion of 375 mg/m2 in each of the consolidationcycles (cycle 3 and 4) the maximum concentration was highest after the fourth infusion (cycle 2) with ageometric mean of 347 µg/mL followed by lower geometric 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)). The median elimination half-life in paediatric patients aged 3 years and older was26 days.

The PK characteristics of rituximab in paediatric patients with DLBCL/BL/BAL/BLL were similar to whathas 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 tumor size is related to higher exposure due to lower time dependent clearance, however,systemic exposures impacted by different tumor sizes remain in the range of exposure that was efficaciousand 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 cycles13501 (278-31070) 11609 (135-31157) 11467 (110-27066)(µg*day/mL)

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

Chronic lymphocytic leukaemia

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 1000 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 to 7.51 L).

Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance andhalf-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSAand gender were the most significant covariates to explain inter-individual variability in pharmacokineticparameters. After adjusting for BSA, male subjects had a larger volume of distribution and a fasterclearance than female subjects. The gender-related pharmacokinetic differences are not considered to beclinically relevant and dose adjustment is not required. No pharmacokinetic data are available in patientswith hepatic or renal impairment.

The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg and1000 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 first infusionranged from 157 to 171 μg/mL for 2 × 500 mg dose and ranged from 298 to 341 μg/mL for 2 × 1000 mgdose. Following second infusion, mean Cmax ranged from 183 to 198 μg/mL for the 2 × 500 mg dose andranged from 355 to 404 μg/mL for the 2 × 1000 mg dose. Mean terminal elimination half-life rangedfrom 15 to 16 days for the 2 × 500 mg dose group and 17 to 21 days for the 2 × 1000 mg dose group.

Mean Cmax was 16 to 19% higher following second infusion compared to the first infusion for bothdoses.

The pharmacokinetics of rituximab were assessed following two intravenous doses of 500 mg and 1000mg upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was170 to 175 μg/mL for 2 × 500 mg dose and 317 to 370 μg/mL for 2 × 1000 mg dose. Cmax followingsecond infusion, was 207 μg/mL for the 2 × 500 mg dose and ranged from 377 to 386 μg/mL for the 2 ×1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second course,was 19 days for 2 × 500 mg dose and ranged from 21 to 22 days for the 2 × 1000 mg dose. PK parametersfor rituximab were comparable over the two treatment courses.

The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following thesame dosage regimen (2 × 1000 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 granulomatosis withpolyangiitis and microscopic polyangiitis who received 375 mg/m2 rituximab once weekly for four doses,the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days). Rituximab meanclearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726 L/day) and 4.50 L (range2.25 to 7.39 L) respectively. Maximum concentration during the first 180 days (Cmax), minimumconcentration 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 patients appear similar to what hasbeen observed in rheumatoid arthritis patients.

Based on the population pharmacokinetic analysis of 25 children (6-17 years old) with GPA and MPA whoreceived 375 mg/m2 rituximab once weekly for four doses, the estimated median terminal eliminationhalf-life was 22 days (range, 11 to 42 days). Rituximab mean clearance and volume of distribution were0.221 L/day (range, 0. 0996 to 0.381 L/day) and 2.27 L (range 1.43 to 3.17 L) respectively. Maximumconcentration during the first 180 days (Cmax), minimum concentration at Day 180 (C180) and Cumulativearea 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 inpaediatric patients with GPA or MPA were similar to those in adults with GPA or MPA, once taking intoaccount the BSA effect on clearance and volume of distribution parameters.

The PK parameters in adult PV patients receiving rituximab 1000 mg at Days 1, 15, 168, and 182 aresummarized 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) 3.52 3.52

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

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 and patientswith RA. Following the last two administrations (at day 168 and 182, corresponding to cycle 2), rituximabclearance 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 Bcells 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 lymphoid organsof the foetuses was observed, which persisted post natally and was accompanied by a decrease in IgGlevel in the newborn animals affected. B cell counts returned to normal in these animals within 6 monthsof birth and did not compromise the reaction to immunisation.

Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant forthis molecule. No long-term animal studies have been performed to establish the carcinogenic potential ofrituximab.

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 or femaleswere observed.

Sodium chloride

Tri-sodium citrate dihydrate (E331)

Polysorbate 80 (E433)

Water for injections

No incompatibilities between rituximab and polyvinyl chloride or polyethylene bags or infusion sets havebeen observed.

Unopened vial4 years

Truxima may be stored at temperatures up to a maximum of 30 °C for a single period of up to 10 days,but not exceeding the original expiry date. The new expiry date must be written on the carton. Uponremoval from refrigerated storage, Truxima must not be returned to refrigerated storage.

Diluted product

The prepared infusion solution of rituximab in 0.9% sodium chloride solution is physically andchemically stable for 30 days at 2 °C - 8 °C and subsequently 24 hours at room temperature (≤ 30 °C),or for 10 days at ≤ 30 °C.

The prepared infusion solution of rituximab in 5% glucose solution is physically and chemicallystable for 24 hours at 2 °C - 8 °C and subsequently 12 hours at room temperature (not more than30 °C).

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

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

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

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

Truxima 100 mg concentrate for solution for infusion

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

Truxima 500 mg concentrate for solution for infusion

Clear Type I glass vial with butyl rubber stopper containing 500 mg of rituximab in 50 mL. Pack of 1 vialor 2 (2 x 1) vials (multipack).

Not all pack sizes may be marketed.

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

Use sterile needle and syringe to prepare Truxima. Aseptically withdraw the necessary amount of

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

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

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

Truxima 100 mg concentrate for solution for infusion

EU/1/16/1167/002

Truxima 500 mg concentrate for solution for infusion

EU/1/16/1167/001

EU/1/16/1167/003

Date of first authorisation: 17 February 2017

Date of latest renewal: 15 November 2021

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

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