MABTHERA 100mg 10mg / ml perfusive solution concentrate medication leaflet

MabThera 100 mg concentrate for solution for infusion

MabThera 500 mg concentrate for solution for infusion

MabThera 100 mg concentrate for solution for infusion

Each mL contains 10 mg of rituximab.

Each 10 mL vial contains 100 mg of rituximab.

MabThera 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 andheavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamsterovary) cell suspension culture and purified by affinity chromatography and ion exchange, includingspecific viral inactivation and removal procedures.

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

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

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear, colourless liquid with pH of 6.2 - 6.8 and osmolality of 324 - 396 mOsmol/kg.

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

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

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

MabThera 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.

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

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

See section 5.1 for further information.

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

MabThera 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

MabThera, 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).

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

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

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

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

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

In adult patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids shouldbe considered if MabThera is not given in combination with glucocorticoid-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 thestart of the infusion of MabThera. 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 CLLpatients whose lymphocyte counts are > 25 x 109/L it is recommended to administerprednisone/prednisolone 100 mg intravenous shortly before infusion with MabThera to decrease therate and severity of acute infusion reactions and/or cytokine release syndrome.

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

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 MabThera 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 MabThera (the last dose ofmethylprednisolone may be given on the same day as the first infusion of MabThera). 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 MabThera treatment.

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

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

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

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

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

Non-Hodgkin’s lymphoma

The recommended dose of MabThera 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.

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

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

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

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

Chronic lymphocytic leukaemia

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

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

A course of MabThera consists of two 1000 mg intravenous infusions. The recommended dosage of

MabThera is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusiontwo weeks later.

The need for further courses should be evaluated 24 weeks following the previous course. Retreatmentshould be given at that time if residual disease activity remains, otherwise retreatment should 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 noevidence of therapeutic benefit within this time period.

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

The recommended dosage of MabThera 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 for4 weeks (four infusions in total).

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

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

MabThera should be administered as two 500 mg IV infusions separated by two weeks, followed by a500 mg IV infusion every 6 months thereafter. Patients should receive MabThera for at least 24 monthsafter achievement of remission (absence of clinical signs and symptoms). For patients who may be athigher risk for relapse, physicians should consider a longer duration of MabThera maintenance therapy,up to 5 years.

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

The recommended dosage of MabThera for the treatment of pemphigus vulgaris is 1000 mgadministered as an IV infusion followed two weeks later by a second 1000 mg IV infusion incombination with a tapering course of glucocorticoids.

A maintenance infusion of 500 mg IV should 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 IV. The healthcare provider should also considerresuming 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.

Non-Hodgkin’s lymphoma

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

Lymphome Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dosage of

MabThera is 375 mg/m2 BSA, administered as an IV infusion. No MabThera dose adjustments, otherthan by BSA, are required.

The safety and efficacy of MabThera in paediatric patients aged 6 months to less than 18 years of agehas not been established in indications other than previously untreated advanced stage CD20 positive

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

MabThera 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 MabThera administration for non-Hodgkin’s lymphoma paediatric patients

Cycle Day of treatment Administration details

Prephase (COP) No MabThera given -

Induction course 1 Day -2(COPDAM1) (corresponding to Day During the 1st induction course, prednisone is6 of the prephase) given as part of the chemotherapy course, and1st MabThera infusion should be administered prior to MabThera.

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

Induction course 2 Day -2(COPDAM2) 3rd MabThera infusion In the 2nd induction course, prednisone is notgiven at the time of MabThera administration.

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

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

Consolidation Day 1course 2 6th MabThera infusion Prednisone is not given at the time of MabThera(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 MabThera given 1.0 x 109/l and platelets > 100 x 109/l

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

No MabThera 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: Concomitant

Chemotherapy with MabThera

Treatment Patient Staging Administration details

Plan

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 MabThera for induction of remission therapy in paediatric patients withsevere, active GPA or MPA is 375 mg/m2 BSA, administered as an IV infusion once weekly for 4 weeks.

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

MabThera 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).

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

The prepared MabThera solution should be administered as an intravenous infusion through a dedicatedline. It should not be administered as an intravenous push or bolus.

Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4).

Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxiashould have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma should thenbe evaluated 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 (IRR) (section 4.8) usually respond to a reduction in therate of infusion. The infusion rate may be increased upon improvement of symptoms.

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

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

Subsequent doses of MabThera can be infused at an initial rate of 100 mg/h, and increased by100 mg/h increments at 30-minute intervals, to a maximum of 400 mg/h.

Non-Hodgkin’s lymphoma - paediatric patients

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

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

Alternative subsequent, faster, infusion schedule

If patients did not experience a serious infusion-related reaction with their first or subsequent infusions ofa dose of 1000 mg MabThera 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 previousserious infusion reactions to any prior biologic therapy or to rituximab, should not be administered themore rapid infusion.

Hypersensitivity to the active substance or to murine proteins, or to any of the excipients listed in section6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

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

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

All patients treated with MabThera 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 progressive multifocalleukoencephalopathy (PML).

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

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

The physician should be particularly alert to symptoms suggestive of PML that the patient may notnotice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised 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 MabThera must be permanently discontinued. Followingreconstitution of the immune system in immunocompromised patients with PML, stabilisation orimproved outcome has been seen. It remains unknown if early detection of PML and suspension of

MabThera therapy may lead to similar stabilisation or improved outcome.

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

Based on the mechanism of action of MabThera and the knowledge that B-cells play an important role inmaintaining normal immune response, patients have an increased risk of infection following MabTheratherapy (see section 5.1). Serious infections, including fatalities, can occur during therapy with

MabThera (see section 4.8). MabThera should not be administered to patients with an active, severeinfection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severelyimmunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians shouldexercise caution when considering the use of MabThera in patients with a history of recurring or chronicinfections or with underlying 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 MabThera.

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

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

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

Hepatitis B Infections

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

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

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

False negative serologic testing of infections

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

Nile virus and neuroborreliosis.

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

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

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

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

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

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied bybronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. 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 release syndrome should have their infusion interruptedimmediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initialimprovement of clinical symptoms may be followed by deterioration, these patients should be closelymonitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out.

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

Patients with a high tumour burden or with a high number (≥ 25 x 109/L) of circulating malignant cellssuch as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome,should be treated with extreme caution. These patients should be very closely monitored 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 with

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

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

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 MabThera administration, consideration should be given towithholding anti-hypertensive medicines 12 hours prior to the MabThera infusion.

Although MabThera 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. MabThera 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

MabThera therapy.

The safety of immunisation with live viral vaccines, following MabThera therapy has not been studiedfor NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treatedwith MabThera may receive non-live vaccinations; however, with non-live vaccines response rates maybe reduced. In a non-randomised study, adult patients with relapsed low-grade NHL who received

MabThera monotherapy when compared to healthy untreated controls had a lower rate of response tovaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH)neoantigen (4% vs. 76% when assessed for > 2-fold increase in antibody titre). For CLL patients, similarresults are assumable considering similarities between both diseases but that has not been investigated inclinical 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 MabThera.

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

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

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

MabThera 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-marketing setting.

In rheumatoid arthritis most infusion-related events reported in clinical trials were mild to moderate in severity.

The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash,urticaria, hypertension and pyrexia. In general, the proportion of patients experiencing any infusion reaction washigher following the first infusion than following the second infusion of any treatment course. The incidence of

IRR decreased with subsequent courses (see section 4.8). The reactions reported were usually reversible with areduction in rate, or interruption, of MabThera infusion and administration of an anti-pyretic, an antihistamine,and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closelymonitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adversereactions. Depending on the severity of the IRR and the required interventions, temporarily or permanentlydiscontinue MabThera. 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 MabThera.

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

MabThera infusion.

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).

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

Physicians should review the patient’s vaccination status and patients should, if possible, be broughtup-to-date with all immunisations in agreement with current immunisation guidelines prior to initiating

MabThera therapy. Vaccination should be completed at least 4 weeks prior to first administration of

MabThera.

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

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

Patients treated with MabThera may receive non-live vaccinations; however, response rates to non-livevaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated with

MabThera and methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%),reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcalantibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after MabThera ascompared to patients only receiving methotrexate. Should non-live vaccinations be required whilstreceiving MabThera therapy, these should be completed at least 4 weeks prior to commencing the nextcourse of MabThera.

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

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

This medicinal product contains 2.3 mmol (or 52.6 mg) sodium per 10 mL vial and 11.5 mmol (or263.2 mg) sodium per 50 mL vial, equivalent to 2.6% (for 10 mL vial) and 13.2% (for 50 mL vial) of the

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

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

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

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

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

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

DMARD following MabThera. In these patients the rate of clinically relevant infection while on

MabThera was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatmentwith the biologic DMARD.

Due to the long retention time of rituximab in B-cell depleted patients, women of childbearing potentialshould use effective contraceptive methods during and for 12 months following treatment with

MabThera.

IgG immunoglobulins are known to cross the placental barrier.

B-cell levels in human neonates following maternal exposure to MabThera 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 MabThera during pregnancy. Similar effects have been observed in animal studies (seesection 5.3). For these reasons MabThera should not be administered to pregnant women unless thepossible benefit outweighs the potential risk.

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

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

No studies on the effects of MabThera on the ability to drive and use machines have been performed,although the pharmacological activity and adverse reactions reported to date suggest that MabTherawould have 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 MabThera in non-Hodgkin’s lymphoma and CLL is based on data frompatients from clinical trials and from post-marketing surveillance. These patients were treated eitherwith MabThera monotherapy (as induction treatment or maintenance treatment following inductiontreatment) or in combination with chemotherapy.

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

MabThera.

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

The most frequently reported or observed serious adverse reactions were:

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

* Infections, see section 4.4.

* Cardiovascular events, see section 4.4.

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

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

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

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

MedDRA

Very

System Organ Common Common Uncommon Rare Very Rare Not known

Class

Infections and bacterial sepsis, serious viral PML enteroviralinfestations infections, +pneumonia, infection2, meningoencephalitviral infections, +febrile infection, pneumocystis is2, 3+bronchitis +herpes zoster, jirovecii+respiratory tractinfection,fungal infections,infections ofunknownaetiology,+acute bronchitis,+sinusitis,hepatitis B1

Blood and neutropenia, anaemia, coagulation transient increase late neutropenia4lymphatic system leucopenia, +pancytopenia, disorders, in serum IgMdisorders +febrile +granulocytopeni aplastic anaemia, levels4neutropenia, a haemolytic+thrombocytope anaemia,nia lymphadenopathy

Immune system infusion-related hypersensitivity anaphylaxis tumour lysis infusion-relateddisorders reactions5, syndrome, acute reversibleangioedema cytokine release thrombocytopenisyndrome5, a5serum sickness

Metabolism and hyperglycaemia,nutrition weight decrease,disorders oedemaperipheral,face oedema,increased LDH,hypocalcaemia

Psychiatric depression,disorders nervousness

Nervous system paraesthesia, dysgeusia peripheral cranialdisorders hypoaesthesia, neuropathy, neuropathy,agitation, facial nerve loss of otherinsomnia, palsy6 senses6vasodilatation,dizziness,anxiety

Eye disorders lacrimation severedisorder, vision loss6conjunctivitis

Ear and tinnitus, hearing loss6labyrinth ear paindisorders

Cardiac disorders +myocardial +left ventricular severe cardiac heart failure5, 7infarction5, 7, failure, disorders5, 7arrhythmia, +supraventricular+atrial fibrillation, tachycardia,tachycardia, +ventricular+cardiac disorder tachycardia,+angina,+myocardialischaemia,bradycardia

MedDRA

Very

System Organ Common Common Uncommon Rare Very Rare Not known

Class

Vascular hypertension, vasculitisdisorders orthostatic (predominatelyhypotension, cutaneous),hypotension leukocytoclasticvasculitis

Respiratory, bronchospasm5, asthma, interstitial lung respiratory lung infiltrationthoracic and respiratory bronchiolitis disease8 failure5mediastinal disease, obliterans,disorders chest pain, lung disorder,dyspnoea, hypoxiaincreased cough,rhinitis

Gastrointestinal nausea vomiting, abdominal gastro-intestinaldisorders diarrhoea, enlargement perforation8abdominal pain,dysphagia,stomatitis,constipation,dyspepsia,anorexia,throat irritation

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

Musculoskeletal hypertonia,and connective myalgia,tissue disorders arthralgia,back pain,neck pain,pain

Renal and renal failure5urinarydisorders

General disorders fever, tumour pain, infusion site painand chills, flushing,administration asthenia, malaise,site conditions headache cold syndrome,+fatigue,+shivering,+multi-organfailure5

Investigations decreased IgGlevels

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 reported1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL2 see also section infection below3 observed during post-marketing surveillance4 see also section haematologic adverse reactions below5 see also section infusion-related reactions below. Rarely fatal cases reported6 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabTheratherapy7 observed 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 reactions during clinical trials, however, werereported at a similar or lower incidence in the MabThera 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 one totwo hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms includedflushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation,rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia andfeatures of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm,hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases weremyocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.

Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure orsevere cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema,multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratoryfailure were reported at lower or unknown frequencies.T he incidence of infusion-related symptomsdecreased substantially with subsequent infusions and is < 1% of patients by the eighth cycle of

MabThera (containing) treatment.

MabThera 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 the

MabThera-containing arm of randomised studies. Severe infections were reported in about 4% ofpatients treated with MabThera monotherapy. Higher frequencies of infections overall, includinggrade 3 or 4 infections, were observed during MabThera 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 MabThera treatment. The majority ofpatients had received MabThera 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 (progressivemultifocal leukoencephalopathy (PML)), enterovirus (meningoencephalitis) and hepatitis C virus (seesection 4.4.). Cases of fatal PML that occurred after disease progression and retreatment have alsobeen reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority ofwhich were in patients receiving MabThera in combination with cytotoxic chemotherapy. In patientswith relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation andprimary infection) was 2% in R-FC vs 0% FC. Progression of Kaposi’s sarcoma has been observed in

MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred innon-approved indications and the majority of patients were HIV positive.

In clinical trials with MabThera 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 MabTheramaintenance 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 MabThera 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-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), pancytopenia(R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with higher frequencies whencompared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with

MabThera and chemotherapy was not associated with a higher incidence of infections and infestationscompared to patients treated with chemotherapy alone. Studies in previously untreated andrelapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropeniawas prolonged (defined as neutrophil count remaining below 1x109/L between Day 24 and 42 after thelast dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 daysafter last dose in patients with no previous prolonged neutropenia or who recovered prior to Day 42)following treatment with MabThera plus FC. There were no differences reported for the incidence ofanaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of

MabThera were reported. In the CLL first-line study, Binet stage C patients experienced more adverseevents in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLLstudy grade 3/4 thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% ofpatients in the FC group.

In studies of MabThera 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 MabThera monotherapy were reported in 18.8% ofpatients with the most frequently reported events being hypotension and hypertension. Cases of grade 3or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris duringinfusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders wascomparable between patients treated with MabThera and observation. Cardiac events were reported asserious adverse reactions (including atrial fibrillation, myocardial infarction, left ventricular failure,myocardial ischaemia) in 3% of patients treated with MabThera compared to < 1% on observation. Instudies evaluating MabThera in combination with chemotherapy, the incidence of grade 3 and 4 cardiacarrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrialflutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group(3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera i nfusion orwere associated with predisposing conditions such as fever, infection, acute myocardial infarction orpre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOPgroup was observed in the incidence of other grade 3 and 4 cardiac events including heart failure,myocardial disease and manifestations of coronary artery disease. In CLL, the overall incidence of grade3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in therelapsed/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, experiencedthromboembolic cerebrovascular accidents during the first treatment cycle. There was no differencebetween the treatment groups in the incidence of other thromboembolic events. In contrast, three patients(1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-upperiod. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low both in thefirst-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 recognisedrisk factors for PRES/RPLS, including the patients’ underlying disease, hypertension,immunosuppressive therapy and/or chemotherapy.

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving

MabThera for treatment of non-Hodgkin’s lymphoma. In the majority of these cases, MabThera wasadministered with chemotherapy.

In the clinical trial evaluating MabThera 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 MabThera groups. In the observation group, the median IgGlevel subsequently increased to above the LLN, but remained constant in the MabThera group. Theproportion of patients with IgG levels below the LLN was about 60% in the MabThera group throughoutthe 2-year treatment period, while it decreased in the observation group (36% after 2 years).

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

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

Patient subpopulations - MabThera monotherapy

Elderly (65 years and above):

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

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

The percentage of patients reporting adverse reactions upon re-treatment with further courses of

MabThera was similar to the percentage of patients reporting adverse reactions upon initial exposure(any grade and grade 3/4 adverse reactions).

Patient subpopulations - MabThera combination therapy

Elderly (65 years and above)

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

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

A total of 309 paediatric patients received MabThera and were included in the safety analysispopulation. Paediatric patients randomised to the LMB chemotherapy arm with MabThera, or enrolled inthe single arm part of the study, were administered MabThera at a dose of 375 mg/m2 BSA and receiveda total of six IV infusions of MabThera (two during each of the two induction courses and one duringeach of the two consolidation courses of the LMB scheme).

The safety profile of MabThera in paediatric patients (aged 6 months to less than 18 years old) withpreviously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL was generally consistent intype, nature and severity with the known safety profile in adult NHL and CLL patients. Addition of

MabThera to chemotherapy did result in an increased risk of some events including infections (includingsepsis) compared to chemotherapy only.

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

The safety profile of MabThera in patients with moderate to severe rheumatoid arthritis (RA) issummarised in the sections below. In clinical trials more than 3100 patients received at least onetreatment course and were followed for periods ranging from 6 months to over 5 years; approximately2400 patients received two or more courses of treatment with over 1000 having received 5 or morecourses. The safety information collected during post marketing experience reflects the expected adversereaction profile as seen in clinical trials for MabThera (see section 4.4).

Patients received 2 x 1000 mg of MabThera separated by an interval of two weeks; in addition tomethotrexate (10-25 mg/week). MabThera 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 frequencygrouping, undesirable effects are presented in order of decreasing seriousness.

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

The most frequent adverse reactions considered due to receipt of MabThera 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 MabThera, progressivemultifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like reaction have beenreported during post marketing experience.

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

MedDRA System Very Common Common Uncommon Rare Very rare Not known

Organ Class

Infections and upper respiratory bronchitis, PML, serious viralinfestations tract infection, sinusitis, reactivation of infection1, 2,urinary tract gastroenteritis, hepatitis B enteroviralinfections tinea pedis meningoencephalitis2

Blood and neutropenia3 late serumlymphatic system neutropenia4 sickness-likedisorders reaction

MedDRA System Very Common Common Uncommon Rare Very rare Not known

Organ Class

Immune system 5infusion-related 5infusion-relateddisorders reactions reactions

General (hypertension, (generaliseddisorders and nausea, rash, oedema,administration pyrexia, pruritus, bronchospasm,site conditions urticaria, throat wheezing,irritation, hot laryngeal oedema,flush, angioneurotichypotension, oedema,rhinitis, rigors, generalisedtachycardia, pruritus,fatigue, anaphylaxis,oropharyngeal anaphylactoidpain, o edema reaction)peripheral,erythema)

Metabolism and hyper-nutrition cholesterolemiadisorders

Psychiatric depression,disorders anxiety

Nervous system headache paraesthesia,disorders 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

Musculoskeletal arthralgia /disorders and musculoskeletalconnective tissue pain,disorders osteoarthritis,bursitis

Investigations decreased IgM decreased IgGlevels6 levels61 See also section infections below.2 Observed during post-marketing surveillance3 Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials4 Frequency category derived from post-marketing data.5 Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRs may occur as aresult of hypersensitivity and/or to the mechanism of action.6 Includes observations collected as part of routine laboratory monitoring.7 Includes fatal cases

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

The most frequent adverse reactions following receipt of MabThera in clinical studies were IRRs(refer to Table 4). Among the 3 189 patients treated with MabThera, 1 135 (36%) experienced at leastone IRR with 733/3 189 (23%) of patients experiencing an IRR following first infusion of the firstexposure to MabThera. The incidence of IRRs declined with subsequent infusions. In clinical trialsfewer than 1% (17/3 189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs andno deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leadingto withdrawal decreased by course and were rare from course 3 onwards. Premedication withintravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2and 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 MabThera 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 of

MabThera. 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 in

MabThera 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 IV antibiotics was approximately 4 per 100 patient years. The rate of seriousinfections did not show any significant increase following multiple courses of MabThera. Lowerrespiratory tract infections (including pneumonia) have been reported during clinical trials, at a similarincidence in the MabThera 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 MabThera for the treatment of autoimmune diseases. This includes rheumatoid arthritis andoff-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and vasculitis.

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

Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving

MabThera (see Section 4.4).

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

Neurologic events

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

Events of neutropenia were observed with MabThera treatment, the majority of which were transientand mild or moderate in severity. Neutropenia can occur several months after the administration of

MabThera (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1 382) of MabThera treated patients and0.27% (2/731) of placebo 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 MabThera. There was no increased rate in overall infections or serious infectionsafter the development of low IgG or IgM (see section 4.4).

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

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

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

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

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

MabThera group and at a higher frequency than the comparator group.

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

Table 5 Adverse reactions occurring at 6-months in ≥ 5% of adult patients receiving

MabThera in GPA/MPA Study 1 (Rituximab n=99), at a higher frequency than thecomparator group, or during post-marketing surveillance

MedDRA System Organ Class Very Common Common Not known

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

Blood and lymphatic system thrombocytopeniadisorders

Immune system disorders cytokine release syndrome

Metabolism and nutrition hyperkalaemiadisorders

Psychiatric disorders insomnia

Nervous system disorders dizziness,tremor

Vascular disorders hypertension flushing

Respiratory, thoracic and cough, nasal congestionmediastinal disorders dyspnoea,epistaxis

Gastrointestinal disorders diarrhoea dyspepsia,constipation

Skin and subcutaneous tissue acnedisorders

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

General disorders and oedema peripheraladministration site conditions

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

In GPA/MPA Study 2, a total of 57 adult patients with severe, active GPA and MPA were treated with

MabThera for the maintenance of remission (see section 5.1).

Table 6 Adverse reactions occurring in ≥ 5% of adult patients receiving MabThera in GPA/MPA

Study 2 (Rituximab n=57), at a higher frequency than the comparator group, or duringpost-marketing surveillance

MedDRA System Organ Class Very Common Common Not known

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

Respiratory, thoracic and dyspnoeamediastinal disorders

Gastrointestinal disorders diarrhoea

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

Injury, poisoning and infusion-related reactions3procedural complications1 Observed during post-marketing surveillance.2 See also section infections below.3 Details on infusion-related reactions are provided in the description of selected adverse reactions section.

The overall safety profile was consistent with the well-established safety profile for MabThera inapproved autoimmune indications, including GPA/MPA. Overall, 4% of patients in the MabThera armexperienced adverse events leading to discontinuation. Most adverse events in the MabThera arm weremild or moderate in intensity. No patients in the MabThera arm had fatal adverse events.

The most commonly reported events considered as adverse reactions were infusion-relatedreactions and infections.

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

MabThera in RA and GPA/MPA and no new adverse reactions were reported.

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

MPA. The overall study period consisted of a 6-month remission induction phase with a minimum18-month follow-up, up to 4.5 years overall. During the follow-up phase, MabThera was given at thediscretion of the investigator (17 out of 25 patients received additional MabThera treatment).

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

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

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

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

In GPA/MPA Study 1 (adult induction of remission study), IRRs were defined as any adverse eventoccurring within 24 hours of an infusion and considered to be infusion-related by investigators in thesafety population. Of the 99 patients treated with MabThera, 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. MabThera was given in combination with intravenousglucocorticoids which may reduce the incidence and severity of these events.

In GPA/MPA Study 2 (adult maintenance study), 7/57 (12%) patients in the MabThera 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%). All IRR symptoms were mild ormoderate and most of them were reported from the SOCs Respiratory, Thoracic and Mediastinal

Disorders and Skin and Subcutaneous Tissue disorders.

In the clinical trial in paediatric patients with GPA or MPA, the reported IRRs were predominantly seenwith the first infusion (8 patients [32%]), and then decreased over time with the number of MabTherainfusions (20% with the second infusion, 12% with the third infusion and 8% with the fourth infusion).

The most common IRR symptoms reported during the remission induction phase were: headache, rash,rhinorrhoea and pyrexia (8%, for each symptom). The observed symptoms of IRRs were similar to thoseknown in adult GPA or MPA patients treated with MabThera. The majority of IRRs were Grade 1 and

Grade 2, there were two non-serious Grade 3 IRRs, and no Grade 4 or 5 IRRs reported. One serious Grade2 IRR (generalised oedema 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% CI 197 - 285) at the 6-month primary endpoint. Infections were predominately mild to moderateand consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections. Therate of serious infections was approximately 25 per 100 patient years. The most frequently reportedserious infection in the MabThera group was pneumonia at a frequency of 4%.

In GPA/MPA Study 2, 30/57 (53%) patients in the MabThera 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 MabThera 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 MabTheragroup was mild or moderate bronchitis.

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

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

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

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

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

In GPA/MPA Study 1, cardiac events occurred at a rate of approximately 273 per 100 patient years(95% CI 149-470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100patient years (95% CI 3 -15). The most frequently reported events were tachycardia (4%) and atrialfibrillation (3%) (see section 4.4).

Neurologic events

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

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

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

In GPA/MPA Study 1, at 6 months, in the MabThera 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 ordecreases in total immunoglobulin, IgG, IgM or IgA levels were observed throughout the trial.

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

Three patients received treatment with intravenous immunoglobulin (IV-IG). Based on limited data, nofirm conclusions can be drawn regarding whether prolonged low IgG and IgM led to an increased risk ofserious infection in these patients. The consequences of long term B-cell depletion in paediatric patientsare unknown.

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

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

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

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

The safety profile of MabThera in combination with short-term, low-dose glucocorticoids in thetreatment of patients with pemphigus vulgaris was studied in a Phase 3, randomised, controlled,multicentre, open-label study in pemphigus patients that included 38 pemphigus vulgaris (PV)patients randomised to the MabThera group (PV Study 1). Patients randomised to the MabTheragroup received an initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15.

Maintenance doses of 500 mg IV were administered at months 12 and 18. Patients could receive1000 mg IV at the time of relapse (see section 5.1).

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

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

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

The adverse reactions from PV Studies 1 and 2 with a frequency categorisation of 'common' or 'verycommon' are presented in Table 7. In PV Study 1, adverse reactions were defined as adverse eventswhich occurred at a rate of ≥ 5% among MabThera-treated PV patients, with a ≥ 2% absolute differencein incidence between the MabThera-treated group and the standard-dose prednisone group up to Month24. No patients were withdrawn due to adverse reactions in Study 1. In PV Study 2, adverse reactionswere defined as adverse events occurring in ≥ 5% of patients in the MabThera arm and assessed asrelated.

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

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

MedDRA Very Common Common Not known

System Organ Class

Infections and infestations upper respiratory tract herpes virus infection, serious viralinfection herpes zoster, infection1, 2,oral herpes, enteroviralconjunctivitis, meningoencephalitis1nasopharyngitis,oral candidiasis,urinary tract infection

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

Psychiatric disorders persistent depressive major depression,disorder irritability

Nervous system disorders headache dizziness

Cardiac disorders tachycardia

Gastrointestinal disorders abdominal pain upper

Skin and subcutaneous alopecia pruritus,tissue disorders urticaria,skin disorder

Musculoskeletal and musculoskeletal pain,connective tissue disorders arthralgia,back pain

General disorders and fatigue,administration site asthenia,conditions pyrexia

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

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

In PV Study 1, infusion-related reactions were common (58%). Nearly all infusion-related reactionswere mild to moderate. The proportion of patients experiencing an infusion-related reaction was 29%(11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third,and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-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,and fourth infusions, respectively. In 11/15 patients who experienced at least one IRR, the IRRs were

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

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

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

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

PV Study 2, in the MabThera 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 IV methylprednisolone premedicationinfusion.

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

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

Limited experience with doses higher than the approved dose of intravenous MabThera formulation isavailable from clinical trials in humans. The highest intravenous dose of MabThera 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 MabThera 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 and antibody drug conjugates,

ATC code: L01FA01

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-B-cells,normal plasma cells or other normal tissue. This antigen does not internalise upon antibody binding andis not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen and, thus, doesnot compete for antibody binding.

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

Peripheral B-cell counts declined below normal following completion of the first dose of MabThera. 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 MabThera 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 MabThera 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 MabThera. In patients with GPA or MPA, the number of peripheral blood

B-cells decreased to < 10 cells/μL after two weekly infusions of rituximab 375 mg/m2, and remained atthat level in most patients up to the 6 month timepoint. The majority of patients (81%) showed signs of

B-cell return, with counts > 10 cells/μL by Month 12, increasing to 87% of patients by Month 18.

Clinical efficacy and safety 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 MabThera 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< 3 months) 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 or absence of bulky disease, normal or high LDH nor presence of extranodaldisease had a statistically significant effect (Fisher’s exact test) on response to MabThera. 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 multi-centre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular

B-cell NHL received 375 mg/m2 of MabThera as intravenous infusion weekly for eight doses. The ORRwas 57% (95% Confidence interval (CI); 41% - 73%; CR 14%, PR 43%) with a projected median TTPfor responding patients of 19.4 months (range 5.3 to 38.9 months).

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

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

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

In an open-label randomised trial, a total of 322 previously untreated patients with follicular lymphomawere randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2, vincristine1.4 mg/m2 up to a maximum of 2 mg on Day 1, and prednisolone 40 mg/m2/day on days 1 -5) every3 weeks for 8 cycles or MabThera 375 mg/m2 in combination with CVP (R-CVP). MabThera wasadministered 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 53 months.

R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment failure(27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour response(CR, CRu, PR) was significantly higher (p< 0.0001 Chi-Square test) in the R-CVP group (80.9%) thanthe CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to disease progressionor death compared to CVP, 33.6 months and 14.7 months, respectively (p < 0.0001, log-rank test). Themedian duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVPgroup (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 MabThera 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 fourstudies are summarised in Table 8.

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

Treatment, Median Median OS

Study FU, CR,

N ORR, % TTF/PFS/ EFS, rates,months % months %

Median TTP: 53-months

CVP, 159 57 10 14.7 71.1

M39021 R-CVP, 162 53 81 41 33.6 80.9

P< 0.0001 p=0.029

Median TTF: 2.6 18-months

CHOP, 205 90 17 years 90

GLSG’00 18

R-CHOP, 223 96 20 Not reached 95p < 0.001 p = 0.01648-months

Median PFS: 28.8

MCP, 96 75 25 74

OSHO-39 47 Not reached

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

CHVP-IFN, 42-months

Median EFS: 36183 85 49

FL2000 42 Not reached 84

R-CHVP-IFN, 94 76 p < 0.0001 91175 p = 0.029

EFS - Event Free Survival

TTP - Time to progression or death

PFS - Progression-Free Survival

TTF - Time to Treatment Failure

OS rates - survival rates at the time of the analyses

In a prospective, open label, international, multi-centre, phase III trial 1 193 patients with previouslyuntreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP(n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1 078 patients respondedto induction therapy, of which 1 018 were randomised to MabThera maintenance therapy (n=505) orobservation (n=513). The two treatment groups were well balanced with regards to baselinecharacteristics and disease status. MabThera maintenance treatment consisted of a single infusion of

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

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

Table 9 Overview of efficacy results for MabThera 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 MabThera Observation MabThera

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 < 0.0001<hazard ratio (95% CI) 0.61 (0.46, 0.80) 0.66 (0.55, 0.78)risk reduction 39% 34%

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

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

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

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

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

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

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

In a prospective, open label, international, multi-centre, phase III trial, 465 patients withrelapsed/refractory follicular lymphoma were randomised in a first step to induction therapy witheither CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or MabThera 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 MabThera maintenance therapy(n=167) or observation (n=167). MabThera maintenance treatment consisted of a single infusion of

MabThera 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 test of CRversus PR versus non-response (p < 0.0001)

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

For patients randomised to the maintenance phase of the trial, the median observation time was28 months from maintenance randomisation. Maintenance treatment with MabThera 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 MabThera maintenance arm compared to14.3 months in the observation arm. Using a cox regression analysis, the risk of experiencing progressivedisease or death was reduced by 61% with MabThera maintenance treatment when compared toobservation (95% CI; 45%-72%). Kaplan-Meier estimated progression-free rates at 12 months were 78%in the MabThera maintenance group vs. 57% in the observation group. An analysis of overall survivalconfirmed the significant benefit of MabThera maintenance over observation (p=0.0039 log-rank test).

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

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

Efficacy Parameter Kaplan-Meier Estimate of Risk

Median Time to Event (Months) Reduction

Observation MabThera Log-Rank(N = 167) (N=167) p value

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

Overall survival NR NR 0.0039 56%

Time to new lymphoma 20.1 38.8 < 0.0001 50%treatment

Disease-free survivala 16.5 53.7 0.0003 67%

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 MabThera 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). MabThera 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, MabThera maintenance treatment provided a significant benefit in terms ofoverall survival for both patients responding to CHOP and patients responding to R-CHOP, althoughlonger follow-up is required to confirm this observation.

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

In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years)with diffuse large B-cell lymphoma received standard CHOP chemotherapy (cyclophosphamide750 mg/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 MabThera 375 mg/m2 plus

CHOP (R-CHOP). MabThera 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 amedian follow-up duration of approximately 31 months. The two treatment groups were well balanced inbaseline disease characteristics and disease status. The final analysis confirmed that R-CHOP treatmentwas associated with a clinically relevant and statistically significant improvement in the duration ofevent-free survival (the primary efficacy parameter; where events were death, relapse or progression oflymphoma, or institution of a new anti-lymphoma treatment) (p=0.0001). Kaplan Meier estimates of themedian duration of event-free survival were 35 months in the R-CHOP arm compared to 13 months inthe CHOP arm, representing a risk reduction of 41%. At 24 months, estimates for overall survival were68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequent analysis of the durationof overall survival, carried out with a median follow-up duration of 60 months, confirmed the benefit of

R-CHOP over CHOP treatment (p=0.0071), representing a risk reduction of 32%.

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

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

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 MabThera in combination with

FC (R-FC). MabThera 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 least6 months) 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-rank test) (Table 12a). The benefit in terms of PFS was consistently observed in most patientsubgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 12b).

Table 12a First-line treatment of chronic lymphocytic leukaemia

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

Efficacy Parameter Kaplan-Meier Estimate of Risk

Median Time to Event (Months) Reduction

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

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

Overall survival NR NR 0.0319 27%

Event free survival 31.3 51.8 < 0.0001 44%

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

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

Duration of response* 36.2 57.3 < 0.0001 44%

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

Time to new treatment 47.2 69.7 < 0.0001 42%

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

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

**: only applicable to patients achieving a CR

Table 12b First-line treatment of chronic lymphocytic leukaemia

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

Progression-free survival (PFS) Number of Hazard Ratio p-value (Waldpatients (95% CI) test, notadjusted)

FC R-FC

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

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

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

CI: Confidence Interval

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

Table 13 Treatment of relapsed/refractory chronic lymphocytic leukaemia - overview ofefficacy results for MabThera plus FC vs. FC alone (25.3 months medianobservation time)

Efficacy Parameter Kaplan-Meier Estimate of Risk

Median Time to Event (Months) Reduction

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

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

Overall survival 51.9 NR 0.2874 17%

Event free survival 19.3 28.7 0.0002 36%

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

CR rates 13.0% 24.3% 0.0007 n.a.

Duration of response * 27.6 39.6 0.0252 31%

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

Time to new CLL treatment 34.2 NR 0.0024 35%

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

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

**: only applicable to patients achieving a CR;

Results from other supportive studies using MabThera 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 MabThera with any chemotherapy.

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

A multicentre, open-label, randomised study of Lymphome Malin B (LMB) chemotherapy(corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin,etoposide and triple drug [methotrexate/cytarabine/ corticosteroid] intrathecal therapy) alone or incombination with MabThera was conducted in paediatric patients with previously untreated advancedstage CD20 positive DLBCL/BL/BAL/BLL. Advanced stage is defined as Stage III with elevated LDHlevel (“B-high”), [LDH > twice the institutional upper limit of the adult normal values (> Nx2)] or anystage IV or BAL. Patients were randomised to receive either LMB chemotherapy or six IV infusions of

MabThera at a dose of 375 mg/m2 BSA in combination with LMB chemotherapy (two during each ofthe two induction courses and one during each of the two consolidation courses) as per the LMBscheme. A total of 328 randomised patients were included in the efficacy analyses, of which one patientunder 3 years of age received MabThera in combination with LMB chemotherapy.

The two treatment arms, LMB (LMB chemotherapy) and R-LMB (LMB chemotherapy with MabThera),were well balanced with regards to baseline characteristics. Patients had a median age of 7 and 8 yearsin the LMB arm and R-LMB arm, respectively. Approximately half of patients were in Group B (50.6%in the LMB arm and 49.4% in the R-LMB arm), 39.6% in Group C1 in both arms, and 9.8% and 11.0%were in Group C3 in the LMB and R-LMB arms, respectively. Based on Murphy staging, most patientswere 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 botharms) had bone marrow 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 wasdefined as occurrence of progressive disease, relapse, second malignancy, death from any cause, ornon-response as evidenced by detection of viable cells in residue after the second CYVE course,whichever occurs first. The secondary efficacy endpoints were OS and CR (complete remission).

At the pre-specified interim analysis with approximately 1 year of median follow-up, 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, andadjusted Cox HR 0.33 (95% CI, 0.14 - 0.79). Upon IDMC (independent data monitoring committee)recommendation based on this result, the randomisation was halted and patients in the LMB arm wereallowed to cross over to receive MabThera.

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

Table 14: Overview of Primary Efficacy Results (ITT population)

Analysis LMB 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 MabThera addition to LMB chemotherapyover LMB chemotherapy alone, with an EFS HR 0.32 (90% CI 0.17 - 0.58) from a Cox regressionanalysis adjusting for national group, histology, and therapeutic group. While no major differences innumbers of patients achieving CR was observed between the two treatment groups, the benefit of

MabThera 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 with

MabThera in all subsets of the paediatric population with follicular lymphoma and CLL, and in thepaediatric population from birth to < 6 months of age in CD20 positive diffuse large B-cell lymphoma.

See Section 4.2 for information on paediatric use.

Clinical efficacy and safety in rheumatoid arthritis

The efficacy and safety of MabThera 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). MabThera was administered as two IVinfusions separated by an interval of 15 days. Patients received 2 x 1000 mg intravenous infusions of

MabThera 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 beyond

Week 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 MabThera between weeks 24and 56, under an open label extension study protocol.

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

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

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 MabThera+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 Response 44 (22%) 193 (65%)***(Good/Moderate)

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

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

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

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

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

In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitortherapies, receiving MabThera 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 MabThera either as rescue betweenweeks 16-24 or in the extension trial, before Week 56. A higher proportion of patients receiving theoriginal MabThera/MTX treatment also had no erosive progression over 56 weeks (Table 16).

Table 16 Radiographic outcomes at 1 year (mITT population)

Placebo+MTX MabThera+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 radiographic 46% 53%, NSchange

Proportion of patients with no erosive change 52% 60%, NS150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX by one year

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

Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis at2 years in Trial 1 demonstrated significantly reduced progression of structural joint damage in patientsreceiving MabThera 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 observedin patients treated with MabThera compared to patients treated with methotrexate alone. The proportionsof MabThera treated patients showing a minimal clinically important difference (MCID) in HAQ-DI(defined as an individual total score decrease of > 0.22) was also higher than among patients receivingmethotrexate alone (Table 17).

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

Further, 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† Placebo+MTX MabThera+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 -9.1***n=197 n=294

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

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

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

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

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

Efficacy outcomes in MabThera 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 to seronegativepatients (p=0.0312 and p=0.0096) (Table 18). These findings were replicated at Week 48, whereautoantibody seropositivity also significantly increased the probability of achieving ACR70. At Week 48seropositive patients were 2-3 times more likely to achieve ACR responses compared to seronegativepatients. Seropositive patients also had a significantly greater decrease in DAS28-ESR compared toseronegative 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 MabThera 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

EULAR responses which was evident in all patient populations studied (Figure 2). Sustainedimprovement in physical function as indicated by the HAQ-DI score and the proportion of patientsachieving MCID for HAQ-DI were observed.

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

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

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

The European Medicines Agency has waived the obligation to submit the results of studies with

MabThera in all subsets of the paediatric population with autoimmune arthritis. See Section 4.2 forinformation on paediatric use.

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

Adult induction of remission treatment

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

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2 mg/kg/day) for3-6 months or MabThera (375 mg/m2) once weekly for 4 weeks. All patients in the cyclophosphamidearm received azathioprine maintenance therapy in during follow-up. Patients in both arms received1000 mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose glucocorticoid) perday for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day). Prednisonetapering was to be completed by 6 months from the start of trial treatment.

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

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

The trial demonstrated non-inferiority of MabThera to cyclophosphamide for complete remission (CR) at6 months (Table 19).

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

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

MabThera Cyclophosphamide Treatment Difference(n = 99) (n = 98) (MabThera- Cyclophosphamide)

Rate 63.6% 53.1% 10.6%95.1%b CI(−3.2%, 24.3%) a− CI = confidence interval.− * Worst case imputationa Non-inferiority was demonstrated since the lower bound ( − 3.2%) was higher than the pre-determined non-inferiority margin ( − 20%).b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.

Table 20 Complete remission at 6-months by disease status

MabThera Cyclophosphamide Difference (CI95%)

All patients n=99 n=98

Newly diagnosed n=48 n=48

Relapsing n=51 n=50

Complete remission

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

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

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

Worst case imputation is applied for patients with missing data

In the MabThera 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 at18 months. From Month 12 to Month 18, 8 relapses were observed in the MabThera group comparedwith four in the cyclophosphamide group.

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

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

Adult maintenance of remission treatment

A total of 117 patients (88 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associatedvasculitis) in disease remission were randomised to receive azathioprine (59 patients) or MabThera (58patients) in a prospective, multi-centre, controlled, open-label study. Included patients were 21 to75 years of age and had newly diagnosed or relapsing disease in complete remission after combinedtreatment with glucocorticoids and pulse cyclophosphamide. The majority of patients were

ANCA-positive at diagnosis or during the course of their disease; had histologically confirmednecrotizing small-vessel vasculitis with a clinical phenotype of GPA or MPA, or renal limited

ANCA-associated vasculitis; or both.

Remission-induction therapy included IV prednisone, administered as per the investigator’s discretion,preceded in some patients by methylprednisolone pulses, and pulse cyclophosphamide until remissionwas attained after 4 to 6 months. At that time, and within a maximum of 1 month after the lastcyclophosphamide pulse, patients were randomly assigned to receive either MabThera (two 500 mg IVinfusions separated by two weeks (on Day 1 and Day 15) followed by 500 mg IV every 6 months for18 months) or azathioprine (administered orally at a dose of 2 mg/kg/day for 12 months, then 1.5 mg/kg/dayfor 6 months, and finally 1 mg/kg/day for 4 months (treatment discontinuation after these 22 months)).

Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg per day) for at least18 months after randomisation. 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 MabTherainfusion or azathioprine dose). Pneumocystis jirovecii pneumonia prophylaxis was required for allpatients with CD4+ T-lymphocyte counts less than 250 per cubic millimetre.

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

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

The cumulative incidence rate curves showed that time to first major relapse was longer in patientswith MabThera 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 MabThera treated patients from the maintenance therapy clinical trialdeveloped ADA. There was no apparent trend or negative impact of the presence of ADA on safety orefficacy in the maintenance therapy clinical trial.

Study WA25615 (PePRS) was a multicentre, open-label, single-arm, uncontrolled study in 25 paediatricpatients (≥ 2 to < 18 years old) with severe, active GPA or MPA. The median age of patients in the study

Percentage of Patients with First

Major Relapsewas: 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 IV methylprednisolone (30 mg/kg/day, not exceeding 1 g/day) prior to the first MabThera IVinfusion. If clinically indicated, additional daily doses (up to three), of IV methylprednisolone could begiven. The remission induction regimen consisted of four once weekly IV infusions of MabThera at adose of 375 mg/m2 BSA, on study days 1, 8, 15 and 22 in combination with oral prednisolone orprednisone at 1 mg/kg/day (max 60 mg/day) tapered to 0.2 mg/kg/day minimum (max 10 mg/day) by

Month 6. After the remission induction phase, patients could, at the discretion of the investigator, receivesubsequent MabThera infusions on or after Month 6 to maintain PVAS remission and control diseaseactivity (including progressive disease or flare) or to achieve first remission.

All 25 patients completed all four once weekly IV 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 MabThera inpaediatric GPA and MPA patients (≥ 2 to < 18 years old). The efficacy objectives of the study wereexploratory and principally assessed using the Pediatric Vasculitis Activity Score (PVAS) (Table 21).

Twenty-four out of 25 patients (96%) in Study WA25615 achieved oral glucocorticoid taper to0.2 mg/kg/day (or less than or equal to 10 mg/day, whichever was lower) at or by Month 6 duringthe 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 Month 18 (median = 5 mg[IQR: 1-5]).

During the Overall Study Period, patients received between 4 and 28 infusions of MabThera (up to 4.5yrs [53.8 months]). Patients received up to 375 mg/m2 x 4 of MabThera, approximately every 6 monthsat the discretion of the investigator. In total, 17 out of 25 patients (68%) received additional rituximabtreatment at or post Month 6 until the Common Close Out, 14 out of these 17 patients received additionalrituximab treatment between Month 6 and Month 18.

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

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

Month 1 0 0.0%, 13.7%

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

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

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

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

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

* PVAS of 0 and achieved glucocorticoid taper to 0.2 mg/kg/day (or 10 mg/day, whichever is lower) atthe assessment time-point.αthe efficacy results are exploratory and no formal statistical testing was performed for these endpoints

MabThera, treatment (375 mg/m2 x 4 infusions) up to Month 6 was identical for all patients. Follow-up treatmentpost Month 6 was at the discretion of the investigator.

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

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

The European Medicines Agency has waived the obligation to submit the results of studies with

MabThera in paediatric population < 2 years of age in severe, active GPA or MPA. See section 4.2 forinformation on paediatric use.

Clinical efficacy and safety in pemphigus vulgaris

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

Patients were stratified by baseline disease severity (moderate or severe) and randomised 1:1 to receiveeither MabThera and low-dose prednisone or standard-dose prednisone. Patients randomised to the

MabThera group received an initial intravenous infusion of 1000 mg MabThera on Study Day 1 incombination with 0.5 mg/kg/day oral prednisone tapered off over 3 months if they had moderate diseaseor 1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease, and a secondintravenous infusion of 1000 mg on Study Day 15. Maintenance infusions of MabThera 500 mg wereadministered at months 12 and 18. Patients randomised to the standard-dose prednisone group receivedan initial 1 mg/kg/day oral prednisone tapered off over 12 months if they had moderate disease or1.5 mg/kg/day oral prednisone tapered off over 18 months if they had severe disease.

Patients in the MabThera group who relapsed could receive an additional infusion of MabThera1000 mg in combination with reintroduced or escalated prednisone dose. Maintenance and relapseinfusions were administered no sooner than 16 weeks following the previous infusion.

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

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

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

Rituximab + Prednisone

Prednisone N=36 p-value a 95% CIb

N=38

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

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

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

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

In a randomised, double-blind, double-dummy, active-comparator, multicentre study, the efficacy andsafety of MabThera compared with mycophenolate mofetil (MMF) were evaluated in patients withmoderate-to-severe PV receiving 60-120 mg/day oral prednisone or equivalent (1.0-1.5 mg/kg/day) atstudy entry and tapered to reach a dose of 60 or 80 mg/day by Day 1. Patients had a confirmed diagnosisof PV within 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 randomised to treatment with MabThera 1000 mgadministered on Day 1, Day 15, Week 24 and Week 26 or oral MMF 2 g/day for 52 weeks incombination with 60 or 80 mg oral prednisone with the aim of tapering to 0 mg/day prednisone by

Week 24.

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

The study demonstrated the superiority of MabThera over MMF in combination with a tapering course oforal corticosteroids in achieving CRoff corticosteroid ≥ 16 weeks at Week 52 in PV patients (Table 23).

The majority of patients in the mITT population were newly diagnosed (74%) and 26% 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)

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

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

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

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

MMF = Mycophenolate mofetil. CI = Confidence Interval.

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

Patients with established disease = duration of illness ≥ 6 months and received prior treatment for

PV.

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

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

Quality Index) verified the statistically significant results of MabThera compared to MMF. Testing ofsecondary endpoints were controlled for multiplicity.

The cumulative oral corticosteroid dose was significantly lower in patients treated with MabThera.

The median (min, max) cumulative prednisone dose at Week 52 was 2775 mg (450, 22180) in the

MabThera group compared to 4005 mg (900, 19920) in the MMF group (p=0.0005).

The total number of disease flares was significantly lower in patients treated with MabThera 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)

MabThera - treated PV patients tested positive for ADA. There was no apparent negative impact of thepresence of ADA on safety 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 MabThera as a single agent or in combination with CHOP therapy (applied MabThera 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 MabThera was 22 days (range, 6.1 to 52 days). Baseline CD19-positive cellcounts and size of measurable tumour lesions contributed to some of the variability in CL2 of MabTherain data from 161 patients given 375 mg/m2 as an intravenous infusion for 4 weekly doses. Patients withhigher CD19-positive cell counts or tumour lesions had a higher CL2.

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

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

MabThera, administered as an intravenous infusion at a dose of 375 mg/m2 at weekly intervals for4 doses to 203 patients with NHL naive to MabThera, 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 patients3 - 6 months after completion of last treatment.

Upon administration of MabThera 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 - 1 177 µg/mL) after the eighth infusion.

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

In the clinical trial studying paediatric DLBCL/BL/BAL/BLL, the PK was studied in a subset of 35patients aged 3 years and older. The PK was comparable between the two age groups (≥ 3 to < 12 yearsvs. ≥ 12 to < 18 years). After two MabThera IV infusions of 375 mg/m2 in each of the two inductioncycles (cycle 1 and 2) followed by one MabThera IV 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) and58.5 µg/mL (pre-dose Cycle 4, after 3 cycles)). The median elimination half-life in paediatric patientsaged 3 years and older was 26 days.

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

No PK data are available in the ≥ 6 months to < 3 years age group, however, population PK predictionsupports comparable systemic exposure (AUC, Ctrough) in this age group compared to ≥ 3 years (Table24). Smaller baseline tumour size is related to higher exposure due to lower time dependent clearance,however, systemic exposures impacted by different tumour sizes remain in the range of exposure thatwas efficacious and had an acceptable safety profile.

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

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

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

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

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

Chronic lymphocytic leukaemia

MabThera 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 MabThera 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 to7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemicclearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysisrevealed that BSA and gender were the most significant covariates to explain inter-individualvariability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volumeof distribution and a faster clearance than female subjects. The gender-related pharmacokineticdifferences are not considered to be clinically relevant and dose adjustment is not required. Nopharmacokinetic data are available in patients with hepatic or renal impairment.

The pharmacokinetics of rituximab were assessed following two intravenous (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 x 500 mg dose and ranged from 298 to 341 µg/mL for 2 x 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 x 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 IV doses of 500 mg and 1000 mg uponre-treatment in the second course. Mean Cmax for serum rituximab following first infusion was 170 to175 µg/mL for 2 x 500 mg dose and 317 to 370 µg/mL for 2 x 1000 mg dose. Cmax following secondinfusion, was 207 µg/mL for the 2 x 500 mg dose and ranged from 377 to 386 µg/mL for the 2 x1000 mg dose. Mean terminal elimination half-life after the second infusion, following the secondcourse, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose. PKparameters for rituximab were comparable over the two treatment courses.

The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following thesame dosage regimen (2 x 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serumconcentration 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 MabThera once weekly for fourdoses, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days).

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

Based on the population pharmacokinetic analysis of 25 children (6-17 years old) with GPA and MPAwho received 375 mg/m2 MabThera once weekly for four doses, the estimated median terminalelimination half-life was 22 days (range, 11 to 42 days). Rituximab mean clearance and volume ofdistribution were 0.221 L/day (range, 0. 0996 to 0.381 L/day) and 2.27 L (range 1.43 to 3.17 L)respectively. Maximum concentration during the first 180 days (Cmax), minimum concentration at Day180 (C180) and Cumulative area under the curve over 180 days (AUC180) were (median [range]) 382.8(270.6-513.6) µg/mL, 0.9 (0-17.7) µg/mL and 9787 (4838-20446) µg/mL*day, respectively. The PKparameters of rituximab in paediatric patients with GPA or MPA were similar to those in adults with

GPA or MPA, once taking into account the BSA effect on clearance and volume of distributionparameters.

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

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

Parameter Infusion

Cycle1st cycle of 1000 mg 2nd cycle of 1000 mg

Day 1 and Day 15 Day 168 and Day 182

N=67 N=67

Terminal Half-life (days)

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

Clearance (L/day)

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

Central Volume of

Distribution (L) 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 andpatients with RA. Following the last two administrations (at Day 168 and 182, corresponding to cycle2), rituximab clearance decreased while the central volume of distribution remained unchanged.

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

B-cells in peripheral blood and in lymphoid tissue.

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to 100 mg/kg(treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus due torituximab. However, dose-dependent pharmacologic depletion of B-cells in the lymphoid organs of thefoetuses was observed, which persisted postnatally and was accompanied by a decrease in IgG level inthe newborn animals affected. B-cell counts returned to normal in these animals within 6 months ofbirth and did not compromise the reaction to immunisation.

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

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

Sodium citrate (E331)

Polysorbate 80 (E433)

Sodium chloride

Sodium hydroxide (for pH adjustment) (E524)

Hydrochloric acid (for pH adjustment) (E507)

Water for injections

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

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

Unopened vial3 years

* After aseptic dilution in sodium chloride solution

The prepared infusion solution of MabThera in 0.9% sodium chloride solution is physically andchemically stable for 30 days at 2 °C - 8 °C plus an additional 24 hours at ≤ 30 °C.

* After aseptic dilution in D-glucose solution

The prepared infusion solution of MabThera in 5% D-glucose solution is physically and chemicallystable for 24 hours at 2 °C - 8 °C plus an additional 12 hours at room temperature.

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). Do not freeze. Keep the vial in the outer carton in order toprotect from light.

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

MabThera 100 mg concentrate for solution for infusion

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

Pack of 2 vials.

MabThera 500 mg concentrate for solution for infusion

Clear Type I glass vials with butyl rubber stopper containing 500 mg of rituximab in 50 mL.

Pack of 1 vial.

Not all pack sizes may be marketed.

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

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

MabThera, 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. Caremust be taken to ensure the sterility of prepared solutions. Since the medicinal product does notcontain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed.

Parenteral medicinal products should be inspected visually for particulate matter and discolourationprior to administration.

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

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

MabThera 100 mg concentrate for solution for infusion

EU/1/98/067/001

MabThera 500 mg concentrate for solution for infusion

EU/1/98/067/002

Date of first authorisation: 2 June 1998

Date of latest renewal: 20 May 2008

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

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