BLITZIMA 500mg perfusive solution concentrate medication leaflet

Blitzima 100 mg concentrate for solution for infusion

Blitzima 500 mg concentrate for solution for infusion

Blitzima 100 mg concentrate for solution for infusion

Each mL contains 10 mg of rituximab.

Each 10 mL vial contains 100 mg of rituximab.

Blitzima 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 6.3 - 6.8 and osmolality of 329 - 387 mOsmol/kg.

Blitzima is indicated in adults for the following indications:

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

Blitzima maintenance therapy is indicated for the treatment of adult follicular lymphomapatients responding to induction therapy.

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

Blitzima 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.

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

Blitzima in combination with chemotherapy is indicated for the treatment of patients with previouslyuntreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety forpatients previously treated with monoclonal antibodies including Blitzima or patients refractory toprevious Blitzima plus chemotherapy.

See section 5.1 for further information.

Granulomatosis with polyangiitis and microscopic polyangiitis

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

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

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

Rituximab should be administered under the close supervision of an experienced 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 rituximab.

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

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

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

In adult patients with GPA or MPA, methylprednisolone given intravenously for 1 to 3 days at adose of 1000 mg per day is recommended prior to the first infusion of rituximab (the last dose ofmethylprednisolone may be given on the same day as the first infusion of rituximab). This should befollowed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly aspossible based on clinical need) during and after the 4 week induction course of rituximab treatment.

Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for adult patients with

GPA/MPA or PV during and following rituximab treatment, as appropriate according to local clinicalpractice guidelines.

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

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

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

GPA or MPA during and following rituximab treatment, as appropriate.

Non-Hodgkin’s lymphoma

The recommended dose of rituximab in combination with chemotherapy for induction treatmentof previously untreated or relapsed/refractory patients with follicular lymphoma is: 375 mg/m2body surface area per cycle, for up to 8 cycles.

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

* Previously untreated follicular lymphoma

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

* Relapsed/refractory follicular lymphoma

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

* Relapsed/refractory follicular lymphoma

The recommended dose of rituximab 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 rituximab monotherapy for patients who have responded to previous treatmentwith rituximab monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is:375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks(see section 5.1).

Adult diffuse large B cell non-Hodgkin's lymphoma

Rituximab 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 rituximabhave not been established in combination with other chemotherapies in diffuse large B cellnon-Hodgkin’s lymphoma.

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

Chronic lymphocytic leukaemia

The recommended dosage of rituximab in combination with chemotherapy for previously 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 eachsubsequent cycle for 6 cycles in total. The chemotherapy should be given after rituximab infusion.

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

The recommended dosage of rituximab for induction of remission therapy in adult patients with

GPA and MPA is 375 mg/m2 body surface area, administered as an intravenous infusion onceweekly for 4 weeks (four infusions in total).

Following induction of remission with rituximab, maintenance treatment in adult patients with

GPA and MPA should be initiated no sooner than 16 weeks after the last rituximab infusion.

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

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

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

The recommended dosage of rituximab for the treatment of pemphigus vulgaris is 1000 mgadministered as an intravenous infusion followed two weeks later by a second 1000 mg intravenousinfusion in combination with a tapering course of glucocorticoids.

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

Treatment of relapse

In the event of relapse, patients may receive 1000 mg intravenous. The healthcare provider should alsoconsider resuming or increasing the patient’s glucocorticoid dose based on clinical evaluation.

Subsequent infusions may be administered no sooner than 16 weeks following the previous infusion.

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

Non-Hodgkin’s lymphoma

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

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

Lymphome Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dosage ofrituximab is 375 mg/m2 BSA, administered as an intravenous infusion. No rituximab doseadjustments, other than by BSA, are required.

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

DLBCL/BL/BAL/BLL. Only limited data are available for patients under 3 years of age. See section5.1 for further information.

Rituximab should not be used in paediatric patients from birth to < 6 months of age with CD20positive diffuse large B-cell lymphoma (see section 5.1)

Table 1 Posology of rituximab administration for Non-Hodgkin’s lymphoma paediatricpatients

Cycle Day of treatment Administration details

Prephase (COP) No rituximab given -

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

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

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

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

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

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

Maintenance Day 25 to 28 ofcourse 1 (M1) consolidation course 2 Starts when peripheral counts have recovered(CYVE) from consolidation course 2 (CYVE) with

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

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

No rituximab given

ANC = Absolute Neutrophil Count; COP = Cyclophosphamide, Vincristine, Prednisone; COPDAM = Cyclophosphamide,

Vincristine, Prednisolone, Doxorubicin, Methotrexate; CYM = CYtarabine (Aracytine, Ara-C), Methotrexate; CYVE =

CYtarabine (Aracytine, Ara-C), VEposide (VP16)

Table 2 Treatment plan for non-hodgkin’s lymphoma paediatric patients: concomitantchemotherapy with rituximab

Treatment Patient staging Administration detailsplan

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

2), 2 induction courses (COPADM) with

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

Group C Group C1: Prephase followed by 6 courses:

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

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

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

BAL CSF positive, Stage IV CSF and M2)positive

Consecutive courses should be given as soon as blood count recovery and patient’s condition allowsexcept for the maintenance courses which are given at 28 day intervals

BAL = Burkitt leukaemia (mature B-cell acute leukaemia); CSF = Cerebrospinal Fluid; CNS = Central Nervous System;

HDMTX = High-dose Methotrexate; LDH = Lactic Acid Dehydrogenase

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

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

MPA as there is a possibility of an inadequate immune response towards childhood vaccinationsagainst common, vaccine preventable childhood diseases (e.g. measles, mumps, rubella, andpoliomyelitis) (see section 5.1).

Blitzima is for intravenous use.

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

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

Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm orhypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphomashould then be evaluated for evidence of tumour lysis syndrome including appropriate laboratorytests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not berestarted until complete resolution of all symptoms, and normalisation of laboratory values and chest

X-ray findings. At this time, the infusion can be initially resumed at not more than one-half theprevious rate. If the same severe adverse reactions occur for a second time, the decision to stop thetreatment should be seriously considered on a case by case basis.

Mild or moderate infusion-related reactions (IRRs) (section 4.8) usually respond to areduction in the rate of infusion. The infusion rate may be increased upon improvement ofsymptoms.

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

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

Paediatric patients - non-Hodgkin’s lymphoma

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

Subsequent doses of rituximab 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.

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

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

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

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

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

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease(see section 4.4 regarding other cardiovascular diseases).

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

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

Very rare cases of fatal PML have been reported following the use of rituximab. Patients must bemonitored at regular intervals for any new or worsening neurological symptoms or signs that may besuggestive of PML. If PML is suspected, further dosing must be suspended until PML has beenexcluded. The clinician should evaluate the patient to determine if the symptoms are indicative ofneurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML.

Consultation with a neurologist should be considered as clinically indicated.

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

False negative serologic testing of infections

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

Nile virus and neuroborreliosis.

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

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

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

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

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Rituximab is associated with infusion-related reactions, which may be related to release of cytokinesand/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishablefrom acute 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 useof the rituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours afterstarting the first rituximab intravenous infusion. They were characterised by pulmonary events andin some cases included rapid tumour lysis and features of tumour lysis syndrome in addition tofever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied bybronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. Thissyndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia,hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactatedehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acuterespiratory failure may be accompanied by events such as pulmonary interstitial infiltration oroedema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hoursof initiating the first infusion. Patients with a history of pulmonary insufficiency or those withpulmonary tumour infiltration may be at greater risk of poor outcome and should be treated withincreased caution. Patients who develop severe cytokine release syndrome should have their infusioninterrupted immediately (see section 4.2) and should receive aggressive symptomatic treatment.

Since initial improvement of clinical symptoms may be followed by deterioration, these patientsshould be closely monitored until tumour lysis syndrome and pulmonary infiltration have beenresolved or ruled out. Further treatment of patients after complete resolution of signs and symptomshas rarely resulted in repeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (≥ 25 x 109/L) of circulating malignantcells such as patients with CLL, who may be at higher risk of especially severe cytokine releasesyndrome, should be treated with extreme caution. These patients should be very closely monitoredthroughout the first infusion. Consideration should be given to the use of a reduced infusion rate forthe first infusion in these patients or a split dosing over two days during the first cycle and anysubsequent cycles if the lymphocyte count is still > 25 x 109/L.

Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated withrituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in10% of patients) see section 4.8. These symptoms are usually reversible with interruption ofrituximab infusion and administration of an anti-pyretic, an antihistaminic and occasionally oxygen,intravenous sodium chloride 9 mg/mL (0.9%) solution or bronchodilators, and glucocorticoids ifrequired. Please see cytokine release syndrome above for severe reactions.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenousadministration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivityreactions typically occur within minutes after starting infusion. Medicinal products for the treatmentof hypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids,should be available for immediate use in the event of an allergic reaction during administration ofrituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations ofthe cytokine release syndrome (described above). Reactions attributed to hypersensitivity have beenreported less frequently than those attributed to cytokine release.

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

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

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

Although rituximab is not myelosuppressive in monotherapy, caution should be exercised whenconsidering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/Las clinical experience in this population is limited. Rituximab has been used in 21 patients whounderwent autologous bone marrow transplantation and other risk groups with a presumablereduced bone marrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed duringrituximab therapy.

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

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

Physicians should exercise caution when considering the use of rituximab in patients with a historyof recurring or chronic infections or with underlying conditions which may further predisposepatients to serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in subjects receiving rituximab includingfulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxicchemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests thatrituximab treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus(HBV) screening should be performed in all patients before initiation of treatment with rituximab. Atminimum this should include HBsAg-status and HBcAb-status. These can be complemented withother appropriate markers as per local guidelines. Patients with active hepatitis B disease should notbe treated with rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb)should consult liver disease experts before start of treatment and should be monitored and managedfollowing local medical standards to prevent hepatitis B reactivation.

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

The safety of immunisation with live viral vaccines, following rituximab therapy has not beenstudied for NHL and CLL patients and vaccination with live virus vaccines is not recommended.

Patients treated with rituximab may receive non-live vaccinations; however, with non-live vaccinesresponse rates may be reduced. In a non-randomised study, adult patients with relapsed low-grade

NHL who received rituximab monotherapy when compared to healthy untreated controls had a lowerrate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet

Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for > 2-fold increase in antibody titer).

For CLL patients, similar results are assumable considering similarities between both diseases butthat has not been investigated in clinical trials.

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

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

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

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

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

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

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

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in thepost-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trialswere mild to moderate in severity. The most common symptoms were allergic reactions likeheadache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general,the proportion of patients experiencing any infusion reaction was higher following the first infusionthan following the second infusion of any treatment course. The incidence of IRR decreased withsubsequent courses (see section 4.8). The reactions reported were usually reversible with a reductionin rate, or interruption, of rituximab infusion and administration of an anti-pyretic, an antihistamine,and, occasionally, oxygen, intravenous sodium chloride solution or bronchodilators, andglucocorticoids if required. Closely monitor patients with pre-existing cardiac conditions and thosewho experienced prior cardiopulmonary adverse reactions. Depending on the severity of the IRR andthe required interventions, temporarily or permanently discontinue rituximab. In most cases, theinfusion can be resumed at a 50 % reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptomshave completely resolved.

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

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

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/ormyocardial infarction have occurred in patients treated with rituximab. Therefore patients witha history of cardiac disease should be monitored closely (see Infusion-related reactions, above).

Based on the mechanism of action of rituximab and the knowledge that B cells play an importantrole in maintaining normal immune response, patients have an increased risk of infection followingrituximab therapy (see section 5.1). Serious infections, including fatalities, can occur during therapywith rituximab (see section 4.8). Rituximab should not be administered to patients with an active,severe infection (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 rituximab in patients with a history of recurring orchronic infections or with underlying conditions which may further predispose patients to seriousinfection, e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulinlevels are determined prior to initiating treatment with rituximab.

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

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reportedfollowing use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseasesincluding Systemic Lupus Erythematosus (SLE) and vasculitis.

Cases of enteroviral meningoencephalitis including fatalities have been reportedfollowing use of rituximab.

False negative serologic testing of infections

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

West Nile virus and neuroborreliosis.

Hepatitis B Infections

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

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatmentwith rituximab. 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 rituximab. Patients with positive hepatitis B serology (either

HBsAg or HBcAb) should consult liver disease experts before start of treatment and should bemonitored and managed following local medical standards to prevent hepatitis B reactivation.

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

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s syndrome) and

Stevens-Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). Incase of such an event with a suspected relationship to rituximab, treatment should be permanentlydiscontinued.

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

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

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

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

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

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

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

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

Immunomodulatory medicinal products may increase the risk of malignancy. However, availabledata do not suggest an increased risk of malignancy for rituximab used in autoimmune indicationsbeyond the malignancy risk already associated with the underlying autoimmune condition.

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

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

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

Co-administration with methotrexate had no effect on the pharmacokinetics of rituximabin rheumatoid 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 therapeuticmonoclonal antibodies.

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

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

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

IgG immunoglobulins are known to cross the placental barrier.

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

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

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

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

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

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

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

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

The most frequent 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 ADRs reported include hepatitis B reactivation and PML (see section 4.4.)

The frequencies of ADRs reported with rituximab alone or in combination with chemotherapyare summarised in Table 3. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare(< 1/10,000) and not known (cannot be estimated from the available data). Within eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

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

MedDRAsystem Very Uncommoorgan class common Common n Rare Very rare Not known

Infections bacterial sepsis, serious viral PML enteroviraland infections, +pneumonia, infection2 meningoencepinfestations viral +febrile Pneumocysti halitis2, 3infections, infection, s+bronchitis +herpes zoster, jirovecii+respiratorytract infection,fungalinfections,infections ofunknownaetiology,+acutebronchitis,+sinusitis,hepatitis B1

Blood and neutropenia, anaemia, coagulation transient latelymphatic leucopenia, +pancytopenia disorders, increase in neutropenia4system +febrile , aplastic serum IgMdisorders neutropenia +granulocytop anaemia, levels4, enia haemolytic+thrombocyt anaemia,openia lymphadenopathy

Immune infusion-relat hypersensitivi anaphylaxis tumour lysis infusion-relatsystem ed reactions5, ty syndrome, ed acutedisorders angioedema cytokine reversiblerelease thrombocytosyndrome5, penia5serumsickness

Metabolism hyperglycaemand ia, weightnutrition decrease,disorders peripheraloedema, faceoedema,increased

LDH,hypocalcaemia

Psychiatric depression,disorders nervousness,

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

Eye lacrimation severe visiondisorders disorder, loss6conjunctivitis

Ear and tinnitus, ear hearing loss6labyrinth paindisorders

Cardiac +myocardial +left severe heart failure5,disorders Infarction5, 7 , ventricular cardiac 7arrhythmia, failure, disorders 5, 7+atrial +supraventrifibrillation, -culartachycardia, tachycardia,+cardiac +ventriculardisorder tachycardia,+angina,+myocardialischaemia,bradycardia

Vascular hypertension, vasculitisdisorders orthostatic (predominatehypotension, lyhypotension cutaneous),leukocytoclasticvasculitis

Respiratory Bronchospas asthma, interstitial respiratory lung, thoracic m5, bronchioliti lung disease8 failure5 infiltrationand respiratory smediastinal disease, chest obliterans,disorders pain, lungdyspnoea, disorder,increased hypoxiacough,rhinitis

Gastrointest nausea vomiting, abdominal gastro-intestiinal diarrhoea, enlargemen naldisorders abdominal t perforation8pain,dysphagia,stomatitis,constipation,dyspepsia,anorexia,throatirritation

Skin and pruritus, urticaria, severesubcutaneo rash, sweating, bullousus tissue +alopecia night sweats, skindisorders +skin reactions,disorder Stevens-

Johnsonsyndrome,toxicepidermalnecrolysis(Lyell’ssyndrome)8

Musculoske hypertonia,letal, myalgia,connective arthralgia,tissue back pain,disorders neck pain,pain

Renal and renal failure5urinarydisorders

General fever, chills, tumour pain, infusiondisorders asthenia, flushing, siteand headache malaise, painadministrati coldon site syndrome,conditions +fatigue,+shivering,+multi-organ

Failure5

Investigatio decreasedns IgG levels

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

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

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50%of patients in clinical trials, and were predominantly seen during the first infusion, usually in thefirst one to two hours. These symptoms mainly comprised fever, chills and rigors. Othersymptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash,fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension,dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-relatedreactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation,pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiacconditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heartfailure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumourlysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported atlower or unknown frequencies. The incidence of infusion-related symptoms decreasedsubstantially with subsequent infusions and is < 1% of patients by the eighth cycle of rituximab-containing treatment.

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

Localised candida infections as well as Herpes zoster were reported at a higher incidence inthe rituximab-containing arm of randomised studies. Severe infections were reported in about4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall,including grade 3 or 4 infections, were observed during rituximab maintenance treatment upto 2 years when compared to observation. There was no cumulative toxicity in terms ofinfections reported over a 2-year treatment period. In addition, other serious viral infectionseither new, reactivated or exacerbated, some of which were fatal, have been reported withrituximab treatment. The majority of patients had received rituximab in combination withchemotherapy or as part of a haematopoetic stem cell transplant. Examples of these seriousviral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster

Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy(PML)), enterovirus (meningoencephalitis) and hepatitis C virus (see section 4.4.). Cases offatal PML that occurred after disease progression and retreatment have also been reported inclinical trials. Cases of hepatitis B reactivation, have been reported, the majority of whichwere in patients receiving rituximab in combination with cytotoxic chemotherapy. In patientswith relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivationand primary infection) was 2% in R-FC vs. 0% FC. Progression of Kaposi’s sarcoma has beenobserved in rituximab-exposed patients with pre-existing Kaposi’s sarcoma. These casesoccurred in non-approved indications and the majority of patients were HIV positive.

In clinical trials with rituximab monotherapy given for 4 weeks, haematological abnormalitiesoccurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4)neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients.

During rituximab maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) andneutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared toobservation. The incidence of thrombocytopenia was low (< 1%, grade 3/4) and was not differentbetween treatment arms. During the treatment course in studies with rituximab in combination withchemotherapy, 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% inpreviously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) wereusually reported with higher frequencies when compared to chemotherapy alone. However, thehigher incidence of neutropenia in patients treated with rituximab and chemotherapy was notassociated with a higher incidence of infections and infestations compared to patients treated withchemotherapy alone. Studies in previously untreated and relapsed/refractory CLL have establishedthat in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophilcount remaining below 1x109/L between day 24 and 42 after the last dose) or occurred with a lateonset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients withno previous prolonged neutropenia or who recovered prior to day 42) following treatment withrituximab plus FC. There were no differences reported for the incidence of anaemia. Some cases oflate neutropenia occurring more than four weeks after the last infusion of rituximab were reported.

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

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

Cardiovascular reactions during clinical trials with rituximab monotherapy were reported in 18.8%of patients with the most frequently reported events being hypotension and hypertension. Cases ofgrade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectorisduring infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiacdisorders was comparable between patients treated with rituximab and observation. Cardiac eventswere reported as serious adverse events (including atrial fibrillation, myocardial infarction, leftventricular failure, myocardial ischaemia) in 3% of patients treated with rituximab compared to< 1% on observation. In studies evaluating rituximab in combination with chemotherapy, theincidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such astachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) ascompared to the CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in thecontext of a rituximab infusion or were associated with predisposing conditions such as fever,infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. Nodifference between the R-CHOP and CHOP group was observed in the incidence of other grade 3and 4 cardiac events including heart failure, myocardial disease and manifestations of coronaryartery disease. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in thefirst-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).

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

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

FC).

Cases of posterior reversible encephalopathy syndrome (PRES) reversible posteriorleukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visualdisturbance, headache, seizures and altered mental status, with or without associated hypertension. Adiagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had 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 receivingrituximab for treatment of non-Hodgkin’s lymphoma. In the majority of these cases, rituximab wasadministered with chemotherapy.

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

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

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

Patient subpopulations - rituximab monotherapy

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

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

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

ADRs).

Patient subpopulations - rituximab combination therapy

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

CLL.

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

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

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

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

The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) issummarised in the sections below. In clinical trials more than 3,100 patients received at least onetreatment course and were followed for periods ranging from 6 months to over 5 years;approximately 2,400 patients received two or more courses of treatment with over 1,000 havingreceived 5 or more courses. The safety information collected during post-marketing experiencereflects the expected adverse reaction profile as seen in clinical trials for rituximab (see section 4.4).

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

Adverse reactions are listed in Table 4. Frequencies are defined as very common (≥ 1/10), common(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to <1/100), very rare (< 1/10,000) and not known (cannotbe estimated from the available data). Within each frequency grouping, undesirable effects arepresented in order of decreasing seriousness.

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

Table 4 Summary of adverse reactions reported in clinical trials or duringpost-marketing surveillance occurring in patients with rheumatoid arthritisreceiving rituximab

MedDRAsystem organ Verycommon Common Uncommon Rare Very rare Not knownclass

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

Blood and Neutropenia2 late serumlymphatic neutropenia sickness-liksystem 4 edisorders reaction

Immune 5infusion-relate 5infusion-relasystem d reactions ted reactionsdisorders (hypertension, (generalised

General nausea, rash, oedema,disorders and pyrexia, bronchospasadministration pruritus, m, wheezing,site conditions urticaria, throat laryngealirritation, hot oedema,flush, angioneurotichypotension, oedema,rhinitis, rigors, generalisedtachycardia, pruritis,fatigue, anaphylaxis,oropharyngeal anaphylactoipain, peripheral d reaction)oedema,erythma)

Metabolism hypercholesteroland nutritional emiadisorders

Psychiatric depression,disorders anxiety

Nervous headache paraesthesia,system migraine,disorders dizziness,sciatica

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

Gastrointestin dyspepsia,al disorders diarrhoea,gastro-oesophagealreflux, mouthulceration, upper

MedDRAsystem organ Verycommon Common Uncommon Rare Very rare Not knownclassabdominal pain

Skin and alopecia toxicsubcutaneous epidermaltissue necrolysisdisorders (Lyell’ssyndrome),

Stevens-

Johnsonsyndrome7

Musculo- arthralgia /skeletal musculoskeletaldisorders pain,osteoarthritis,bursitis

Investigations decreased IgM decreased IgGlevels6 levels61 See also section infections below2 Observed during post-marketing surveillance3 Frequency category derived from laboratory values collected as part of routine laboratory monitoringin 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 a result of hypersensitivity and/or to the mechanism of action.6 Includes observations collected as part of routine laboratory monitoring.7 Includes fatal cases

Multiple courses of treatment are associated with a similar ADR profile to that observed followingfirst exposure. The rate of all ADRs following first rituximab exposure was highest during the first6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during thefirst treatment course), RA exacerbation and infections all of which were more frequent in the first6 months of treatment.

The most frequent ADRs following receipt of rituximab in clinical trials were IRRs (refer to Table4). Among the 3189 patients treated with rituximab, 1,135 (36%) experienced at least one IRR with733/3,189 (23%) of patients experiencing an IRR following first infusion of the first exposure torituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and nodeaths 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 rituximab infusion in patients withrheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a serious

IRR during or within 24 hours of their first studied infusion were allowed to receive a 2-hourintravenous infusion of rituximab. Patients with a history of a serious infusion reaction to a biologictherapy for RA were excluded from entry. The incidence, types and severity of IRRs were consistentwith that observed historically. No serious IRRs were observed.

The overall rate of infection reported from clinical trials was approximately 94 per 100 patient yearsin rituximab treated patients. The infections were predominately mild to moderate and consistedmostly of upper respiratory tract infections and urinary tract infections. The incidence of infectionsthat were serious or required intravenous antibiotics, was approximately 4 per 100 patient years. Therate of serious infections did not show any significant increase following multiple courses ofrituximab. Lower respiratory tract infections (including pneumonia) have been reported duringclinical trials, at a similar incidence in the rituximab-arms compared to control arms.

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

Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reportedfollowing use of rituximab for the treatment of autoimmune diseases. This includes rheumatoidarthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) andvasculitis.

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

Reactivation of hepatitis B infection has also been very rarely reported in rheumatoid arthritis patientsreceiving rituximab (see section 4.4).

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

Neurologic events

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

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

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and0.27% (2/731) of placebo-treated patients developed severe neutropenia.

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

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

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

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

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

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

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

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

MedDRA system organ class Frequencyadverse event

Urinary tract infection 7%

Bronchitis 5%

Herpes zoster 5%

Nasopharyngitis 5%

Serious viral infection 1,2 Not known

Enteroviral meningoencephalitis 1 Not known

Blood and lymphaticsystem disorders

Thrombocytopenia 7%

Cytokine release syndrome 5%

Hyperkalaemia 5%

Insomnia 14%

Dizziness 10%

Tremor 10%

Hypertension 12%

Flushing 5%

Respiratory, thoracic andmediastinal disorders

Cough 12%

Dyspnoea 11%

Epistaxis 11%

Nasal congestion 6%

Gastrointestinaldisorders

Diarrhoea 18%

Dyspepsia 6%

Constipation 5%

Skin and subcutaneoustissue disorders

Acne 7%

Musculoskeletal and connectivetissue disorders

Muscle spasms 18%

MedDRA system organ class Frequencyadverse event

Arthralgia 15%

Back pain 10%

Muscle weakness 5%

Musculoskeletal pain 5%

Pain in extremities 5%

General disorders andadministration site conditions

Peripheral oedema 16%

Decreased haemoglobin 6%1 Ovserved during post-marketing surveillance.2 See also section infections below.

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

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

GPA/MPA Study 2 (Rituixmab n=57), at a higher frequency than thecomparator group, or during postmarketing surveillance.

MedDRA system organ class

Adverse reaction Frequency

Bronchitis 14%

Rhinitis 5%

Serious viral infection 1, 2 Not known.

Enteroviral meningoencephalitis 1 Not known

General disorders and administration siteconditions

Pyrexia 9%

Influenza-like illness 5%

Oedema peripheral 5%

Diarrhoea 7%

Respiratory, thoracic and mediastinaldisorders

Dyspnoea 9%

Injury, poisoning and proceduralcomplications

Infusion-related reactions3 12%1 Observed during post-marketing surveillance.2 See also section infection below.3 Details on infusion related reactions are provided in the description of selected adverse drug reactionssection.

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

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

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

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

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

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

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

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

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

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

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

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

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 rituximabinfusions (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,rhinorrhea and pyrexia (8%, for each symptom). The observed symptoms of IRRs were similar to thoseknown in adult GPA or MPA patients treated with rituximab. 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

Grade 2 IRR (generalized oedema which resolved with treatment) was reported in one patient (seesection 4.4).

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

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

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

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

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

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

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

In the paediatric clinical trial, no malignancies were reported with a follow-up period of up to 54months.

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 per100 patient years (95% CI 3-15). The most frequently reported events were tachycardia (4%) andatrial fibrillation (3%) (see section 4.4).

Neurologic events

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

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

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

In GPA/MPA Study 1, at 6 months, in the rituximab group, 27%, 58% and 51% of patients withnormal immunoglobulin levels at baseline had low IgA, IgG and IgM levels, respectively, comparedto 25%, 50% and 46% in the cyclophosphamide group. The rate of overall infections and seriousinfections was not increased after the development of low IgA, IgG or IgM.

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

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

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

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

In GPA/MPA Study 2, the incidence of all-grade neutropenia was 0% for rituximab-treated patientsvs. 5% for azathioprine treated patients.

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

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

Day 15. Maintenance doses of 500 mg intravenous were administered at months 12 and 18. Patientscould receive 1000 mg intravenous at the time of relapse (see section 5.1).

In PV Study 2, a randomized, double-blind, double-dummy, active-comparator, multicenter studyevaluating the efficacy and safety of rituximab compared with mycophenolate mofetil (MMF) inpatients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatmentwith rituximab (initial 1000 mg intravenous on Study Day 1 and a second 1000 mg intravenous on

Study Day 15 repeated at Weeks 24 and 26) for up to 52 weeks (see section 5.1).

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

Adverse reactions from PV Studies 1 and 2 are presented in Table 7. In PV Study 1, ADRs weredefined as adverse events which occurred at a rate of ≥ 5% among rituximab-treated PV patients, witha ≥ 2% absolute difference in incidence between the rituximab-treated group and the standard-doseprednisone group up to month 24. No patients were withdrawn due to ADRs in Study 1. In PV Study2, ADRs were defined as adverse events occurring in ≥ 5% of patients in the rituximab arm andassessed as related.

Table 7 Adverse reactions in rituximab-treated pemphigus vulgaris patients in PV

Study 1 (up to Month 24) and PV Study 2 (up to Week 52), or duringpostmarketing surveillance

MedDRA system organclass Very common Common Not known

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

Oral herpes Enteroviral

Conjunctivitis meningoencephalitis 1

Nasopharyngitis

Oral candidiasis

Urinary tractinfection

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

Psychiatric disorders Persistent depressive Major depressiondisorder Irritability

Nervous system disorders Headache Dizziness

Cardiac disorders Tachycardia

Gastrointestinal disorders Abdominal painupper

Skin and subcutaneous Alopecia Pruritustissue disorders Urticaria

Skin disorder

Musculoskeletal, Musculoskeletal painconnective tissue and bone Arthralgiadisorders Back pain

General disorders and Fatigueadministration site Astheniaconditions Pyrexia

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

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

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

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

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

In PV Study 1, 14 patients (37%) in the rituximab group experienced treatment-related infectionscompared to 15 patients (42%) in the standard-dose prednisone group. The most common infectionsin the rituximab group were herpes simplex and zoster infections, bronchitis, urinary tract infection,fungal infection and conjunctivitis. Three patients (8%) in the rituximab group experienced a total of5 serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis,lung infection, Staphylococcal sepsis) and one patient (3%) in the standard-dose prednisone groupexperienced a serious infection (Pneumocystis jirovecii pneumonia).

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

In the post marketing setting, serious viral infection have been reported in PV patients with rituximab.

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

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

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

Limited experience with doses higher than the approved dose of intravenous rituximab formulationis available from clinical trials in humans. The highest intravenous dose of rituximab tested inhumans to date is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. Noadditional safety signals were identified.

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

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

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

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

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

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylatedphosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on > 95% ofall B cell non-Hodgkin’s lymphomas.

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

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

Peripheral B cell counts declined below normal following completion of the first dose of rituximab.

In patients treated for haematological malignancies, B cell recovery began within 6 months oftreatment and generally returned to normal levels within 12 months after completion of therapy,although in some patients this may take longer (up to a median recovery time of 23 monthspost-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in theperipheral blood was observed following two infusions of 1000 mg rituximab separated by a 14 dayinterval. Peripheral blood B cell counts begin to increase from week 24 and evidence for repopulationis observed in the majority of patients by week 40, whether rituximab was administered asmonotherapy or in combination with methotrexate. A small proportion of patients had prolongedperipheral B cell depletion lasting 2 years or more after their last dose of rituximab. In patients with

GPA or MPA, the number of peripheral blood B cells decreased to < 10 cells/μL after two weeklyinfusions of rituximab 375 mg/m2, and remained at that 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 bymonth 12, increasing to 87% of patients by month 18.

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

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

Neither age, sex, lymphoma grade, initial diagnosis, presence nor absence of bulky disease, normalor high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exacttest) on response to rituximab. A statistically significant correlation was noted between responserates and bone marrow involvement. 40% of patients with bone marrow involvement respondedcompared to 59% of patients with no bone marrow involvement (p=0.0186). This finding was notsupported by a stepwise logistic regression analysis in which the following factors were identified asprognostic factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy andbulky disease.

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

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

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

In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (singlelesion ≥ 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m2 of rituximab asintravenous infusion weekly for four doses. The ORR was 36% (CI95% 21% - 51%; CR 3%, PR33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

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

B cell NHL, who had achieved an objective clinical response to a prior course of rituximab, werere-treated with 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. Three of thepatients had received two courses of rituximab before enrolment and thus were given a third coursein the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the

ORR was 38% (CI95% 26% - 51%; 10% CR, 28% PR) with a projected median TTP for respondingpatients of 17.8 months (range 5.4 - 26.6). This compares favourably with the TTP achieved afterthe prior course of rituximab (12.4 months).

In an open-label randomised trial, a total of 322 previously untreated patients with follicularlymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2,vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day ondays 1-5) every 3 weeks for 8 cycles or rituximab 375 mg/m2 in combination with CVP (R-CVP).

Rituximab was administered on the first day of each treatment cycle. A total of 321 patients (162

R-CVP, 159 CVP) received therapy and were analysed for efficacy. The median follow-up ofpatients 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 ofpatients with a tumour response (CR, CRu, PR) was significantly higher (p < 0.0001 Chi-Squaretest) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment with R-CVPsignificantly prolonged the time to disease progression or death compared to CVP, 33.6 monthsand 14.7 months, respectively (p <0.0001, log-rank test). The median duration of response was37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-ranktest).

The difference between the treatment groups with respect to overall survival showed a significantclinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were80.9% for patients in the R-CVP group compared to 71.1% for patients in the CVP group．

Results from three other randomised trials using rituximab in combination with chemotherapyregimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significantimprovements in response rates, time-dependent parameters as well as in overall survival. Keyresults from all four studies are summarised in Table 8.

Table 8 Summary of key results from four phase III randomised studies evaluatingthe benefit of rituximab with different chemotherapy regimens in follicularlymphoma

Study Treatment, Median Median

FU, ORR, % CR, % TTF/PFS/ EFS OS rates,

N months months %

Median TTP: 53-months

M39021 CVP, 159 57 10 14.7 71.1

R-CVP, 162 53 81 41 33.6 80.9

P < 0.0001 p=0.029

Median TTF:

CHOP, 205 2.6 18-months

GLSG’00 R-CHOP, 18 90 17 90223 96 20 years

Not reached 95

P < 0.001 p = 0.016

MCP, 96 Median PFS: 48-months

OSHO‐39 R-MCP, 47 75 25 28.8 Not 74105 92 50 reached 87

P < 0.0001 p = 0.0096

CHVP-IFN,183 85 49 Median EFS: 36 42-months

FL2000 R-CHVP- 42 94 76 Not reached 84

IFN, 175 P < 0.0001 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, multicentre, phase III trial 1193 patients with previouslyuntreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP(n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1078 patientsresponded to induction therapy, of which 1018 were randomised to rituximab maintenance therapy(n=505) or observation (n=513). The two treatment groups were well balanced with regards tobaseline characteristics and disease status. Rituximab maintenance treatment consisted of a singleinfusion of rituximab at 375 mg/m2 body surface area given every 2 months until diseaseprogression or for a maximum period of two years.

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

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

Data from extended follow-up of patients in the study (median follow-up 9 years) confirmed thelong-term benefit of rituximab maintenance therapy in terms of PFS, EFS, TNLT and TNCT (Table9).

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

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

Observation Rituximab Observation Rituximab

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

Primary efficacy

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

Secondary efficacy

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

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

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

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

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

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

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

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

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

Rituximab maintenance treatment provided consistent benefit in all predefined subgroups tested:gender (male, female), age (< 60 years, ≥ 60 years), FLIPI score (≤ 1, 2 or ≥3), induction therapy (R-

CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment (CR,

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

In a prospective, open label, international, multicentre, phase III trial, 465 patients withrelapsed/refractory follicular lymphoma were randomised in a first step to induction therapy witheither CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or rituximabplus CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard tobaseline characteristics and disease status. A total of 334 patients achieving a complete or partialremission following induction therapy were randomised in a second step to rituximab maintenancetherapy (n=167) or observation (n=167). Rituximab maintenance treatment consisted of a singleinfusion of rituximab at 375 mg/m2 body surface area given every 3 months until diseaseprogression or for a maximum period of two years.

The final efficacy analysis included all patients randomised to both parts of the study. After amedian observation time of 31 months for patients randomised to the induction phase, R-CHOPsignificantly improved the outcome of patients with relapsed/refractory follicular lymphoma whencompared to CHOP (see Table 10).

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

Risk

CHOP R‐CHOP p‐value

Reduction1)

Primary efficacy

ORR2) 74% 87% 0.0003 NA

CR2) 16% 29% 0.0005 NA

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

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

For patients randomised to the maintenance phase of the trial, the median observation time was 28months from maintenance randomisation. Maintenance treatment with rituximab led to a clinicallyrelevant and statistically significant improvement in the primary endpoint, PFS, (time frommaintenance randomisation to relapse, disease progression or death) when compared to observationalone (p< 0.0001 log-rank test). The median PFS was 42.2 months in the rituximab maintenancearm compared to 14.3 months in the observation arm. Using a cox regression analysis, the risk ofexperiencing progressive disease or death was reduced by 61% with rituximab maintenancetreatment when compared to observation (95% CI; 45%-72%). Kaplan-Meier estimatedprogression-free rates at 12 months were 78% in the rituximab maintenance group vs. 57% in theobservation group. An analysis of overall survival confirmed the significant benefit of rituximabmaintenance over observation (p=0.0039 log-rank test). Rituximab maintenance treatment reducedthe risk of death by 56% (95% CI; 22%-75%).

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

Kaplan-Meier estimate of

Efficacy parameter median time to event (months) Risk

Observation Rituximab Log-rank reduction(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 lymphomatreatment 20.1 38.8 < 0.0001 50%

Disease‐free survivala 16.5 53.7 0.0003 67%

PFS

CHOP 11.6 37.5 < 0.0001 71%

R-CHOP 22.1 51.9 0.0071 46%

CR 14.3 52.8 0.0008 64%

PR 14.3 37.8 < 0.0001 54%

OS

CHOP NR NR 0.0348 55%

R-CHOP NR NR 0.0482 56%

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

The benefit of rituximab maintenance treatment was confirmed in all subgroups analysed, regardlessof induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR)(Table 11). Rituximab maintenance treatment significantly prolonged median PFS in patientsresponding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p< 0.0001) aswell as in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months,p=0.0071). Although subgroups were small, rituximab maintenance treatment provided a significantbenefit in terms of overall survival for both patients responding to CHOP and patients responding to

R-CHOP, although longer follow-up is required to confirm this observation.

Adult Diffuse large B cell non-Hodgkin’s lymphoma

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

The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had amedian follow-up duration of approximately 31 months. The two treatment groups were wellbalanced in baseline disease characteristics and disease status. The final analysis confirmed that R-

CHOP treatment was associated with a clinically relevant and statistically significant improvement inthe duration of event-free survival (the primary efficacy parameter; where events were death, relapseor progression of lymphoma, or institution of a new anti-lymphoma treatment) (p=0.0001). Kaplan

Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP armcompared to 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months,estimates for overall survival were 68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm.

A subsequent analysis of the duration of overall survival, carried out with a median follow-upduration 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 and0.95 respectively. 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 patientswith relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25mg/m2, cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or rituximab incombination with FC (R-FC). Rituximab was administered at a dosage of 375 mg/m2 during the firstcycle one day prior to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequenttreatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they hadpreviously been treated with monoclonal antibodies or if they were refractory (defined as failure toachieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A totalof 810 patients (403 R-FC, 407 FC) for the first-line study (Table 12a and Table 12b) and 552patients (276 R-FC, 276 FC) for the relapsed/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 55months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis ofoverall survival 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 mostpatient subgroups 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 rituximab plus FC vs. FC alone - 48.1 monthsmedian observation time

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

Number ofpatients Hazard ratio p-value (Waldtest, not

Progression‐free survival (PFS) FC R‐FC (95% CI) adjusted)

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

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

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

CI: Confidence Interval

In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6months in the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). The benefit interms 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 - overviewof efficacy results for rituximab plus FC vs. FC alone (25.3 months medianobservation time)

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

FC R-FC L og-rank(N = 276) (N=276) p value

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

Overall survival 51.9 NR 0.2874 17%

Event free survival 19.3 28.7 0.0002 36%

Response rate (CR, nPR, or PR) 58.0% 69.9% 0.0034 N/A

CR rates 13.0% 24.3% 0.0007 N/A

Duration of response * 27.6 39.6 0.0252 31%

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

Time to new CLL treatment 34.2 NR 0.0024 35%

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; N/A: not applicable

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

**: only applicable to patients achieving a CR;

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

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

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

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

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

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

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

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

LMB arm were allowed to cross over to receive rituximab.

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

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

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

EFS 28 events 10 events

One-sided log-rank test p-value 0.0006

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

OS 20 deaths 8 deaths

One-sided log-rank test p-value 0.0061

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

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

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

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

The European Medicines Agency has waived the obligation to submit the results of studies withrituximab in all subsets of the paediatric population with follicular lymphoma and chroniclymphocytic leukaemia, and in the paediatric population from birth to < 6 months of age in CD20positive diffuse large B-cell lymphoma. See section 4.2 for information on paediatric use.

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

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one ormore TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed accordingto the criteria of the American College of Rheumatology (ACR). Rituximab was administered as twointravenous infusions separated by an interval of 15 days. Patients received 2 x 1000 mg intravenousinfusions of rituximab or placebo in combination with MTX. All patients received concomitant60 mg oral prednisone on days 2-7 and 30 mg on days 8-14 following the first infusion. The primaryendpoint was the proportion of patients who achieved an ACR20 response at week 24. Patients werefollowed beyond week 24 for long-term endpoints, including radiographic assessment at 56 weeksand at 104 weeks. During this time, 81% of patients, from the original placebo group receivedrituximab between weeks 24 and 56, under an open label extension study protocol.

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

Rituximab in combination with methotrexate significantly increased the proportion of patientsachieving at least a 20% improvement in ACR score compared with patients treated 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 ofthe ACR response (tender and swollen joint counts, patient and physician global assessment,disability index scores (HAQ), pain assessment and C-Reactive Proteins (mg/dL).

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

Outcome† Placebo+MTX Rituximab+MTX(2 x 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(Good/Moderate) 44 (22%) 193 (65%)***

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

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

Patients treated with rituximab in combination with methotrexate had a significantly greaterreduction in disease activity score (DAS28) than patients treated with methotrexate alone (Table 15).

Similarly, a good to moderate European League Against Rheumatism (EULAR) response wasachieved by significantly more rituximab treated patients treated with rituximab and methotrexatecompared to patients 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 narrowingscore.

In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNFinhibitor therapies, receiving rituximab in combination with methotrexate demonstratedsignificantly less radiographic progression than patients originally receiving methotrexate alone at56 weeks. Of the patients originally receiving methotrexate alone, 81% received rituximab either asrescue between weeks 16-24 or in the extension trial, before week 56. A higher proportion ofpatients receiving the original rituximab/MTX treatment also had no erosive progression over 56weeks (Table 16).

Table 16 Radiographic outcomes at 1 year (mITT population)

Placebo+MTX Rituximab +MTX2 × 1000 mg

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

Mean change from baseline:

Modified total sharp score 2.30 1.01*

Erosion score 1.32 0.60*

Joint space narrowing score 0.98 0.41**

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

Proportion of patients with no erosive 52% 60%, NSchange150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX byone year

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

Inhibition of the rate of progressive joint damage was also observed long term. Radiographicanalysis at 2 years in Trial 1 demonstrated significantly reduced progression of structural jointdamage in patients receiving rituximab in combination with methotrexate compared to methotrexatealone as well as a significantly higher proportion of patients with no progression of joint damageover the 2-year period.

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

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

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

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

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

Outcome† Placebo+MTX Rituximab+MTX(2 x 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 rituximab in combination with methotrexate showed an enhancedresponse compared to patients negative to both.

Efficacy outcomes in rituximab treated patients were analysed based on autoantibody status priorto commencing treatment. At Week 24, patients who were seropositive to RF and/or anti-CCP atbaseline had a significantly increased probability of achieving ACR20 and 50 responses comparedto seronegative patients (p=0.0312 and p=0.0096) (Table 18). These findings were replicated at

Week 48, where autoantibody seropositivity also significantly increased the probability ofachieving ACR70. At week 48 seropositive patients were 2-3 times more likely to achieve ACRresponses compared to seronegative patients. Seropositive patients also had a significantly greaterdecrease in DAS28-ESR compared to seronegative patients (Figure 1).

Table 18 Summary of efficacy by baseline autoantibody status

Week 24 Week 48

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

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

ACR50 (%) 32.7* 19.8 44.9** 22.8

ACR70 (%) 12.1 5.7 20.9* 6.9

EULAR Response (%) 74.8* 62.9 84.3* 72.3

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

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

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

Treatment with rituximab in combination with methotrexate over multiple courses resulted insustained improvements 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).

Sustained improvement in physical function as indicated by the HAQ-DI score and the proportion ofpatients achieving MCID for HAQ-DI were observed.

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

TNF-inhibitors (n=146)

A total of 392/3095 (12.7%) patients with rheumatoid arthritis tested positive for ADA in clinicaltrials following therapy with rituximab. The emergence of ADA was not associated with clinicaldeterioration or with an increased risk of reactions to subsequent infusions in the majority ofpatients. The presence of ADA may be associated with worsening of infusion or allergic reactionsafter the second infusion of subsequent courses.

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

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

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2 mg/kg/day)for 3-6 months or rituximab (375 mg/m2) once weekly for 4 weeks. All patients in thecyclophosphamide arm received azathioprine maintenance therapy during follow-up. Patients in botharms received 1000 mg of pulse intravenous (IV) methylprednisolone (or another equivalent-doseglucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding80 mg/day). Prednisone tapering was to be completed by 6 months from the start of study treatment.

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

Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and offglucocorticoid therapy. The pre-specified non-inferiority margin for the treatment difference was20%. The trial demonstrated non-inferiority of rituximab to cyclophosphamide for completeremission (CR) at 6 months (Table 19).

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

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

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

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

Table 20 Complete remission at 6-months by disease status

Rituximab Cyclophosphamide Difference (CI 95%)

All patients newly n=99 n=98diagnosed n=48 n=48relapsing n=51 n=50

Complete remission

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

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

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

Worst case imputation is applied for patients with missing data

In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved

CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine formaintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% ofpatients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in therituximab group compared with four in the cyclophosphamide group.

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

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

A total of 117 patients (88 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associatedvasculitis) in disease remission were randomised to receive azathioprine (59 patients) or rituximab (58patients) in a prospective, multi-center, controlled, open-label study. Included patients were 21 to 75years of age and had newly diagnosed or relapsing disease in complete remission after combinedtreatment with glucocorticoids and pulse cyclophosphamide. The majority of patients were ANCA-positive at diagnosis or during the course of their disease; had histologically confirmed necrotizingsmall-vessel vasculitis with a clinical phenotype of GPA or MPA, or renal limited ANCA-associatedvasculitis; or both.

Remission-induction therapy included intravenous prednisone, administered as per the investigator’sdiscretion, preceded in some patients by methylprednisolone pulses, and pulse cyclophosphamide untilremission was attained after 4 to 6 months. At that time, and within a maximum of 1 month after the lastcyclophosphamide pulse, patients were randomly assigned to receive either rituximab (two 500 mgintravenous infusions separated by two weeks (on Day 1 and Day 15) followed by 500 mg intravenousevery 6 months for 18 months) or azathioprine (administered orally at a dose of 2 mg/kg/day for 12months, then 1.5 mg/kg/day for 6 months, and finally 1 mg/kg/day for 4 months (treatmentdiscontinuation after these 22 months)). Prednisone treatment was tapered and then kept at a low dose(approximately 5 mg per day) for at least 18 months after randomization. Prednisone dose tapering andthe decision to stop prednisone treatment after month 18 were left at the investigator’s discretion.

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

CD4+ T-lymphocyte counts less than 250 per cubic millimeter.

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

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

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

Figure 3: Cumulative incidence over time of first major relapse

Percentage of

Patients with

First

Major

Relapse

Survival Time (Months)

Number of Subjects with Major Relapse

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

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

Number of subjects at risk

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

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

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

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

Study WA25615 (PePRS) was a multicenter, open-label, single-arm, uncontrolled study in 25paediatric patients (≥2 to <18 years old) with severe, active GPA or MPA. The median age of patientsin the study was: 14 years (range: 6-17 years) and the majority of patients (20/25 [80%]) were female.

A total of 19 patients (76%) had GPA and 6 patients (24%) had MPA at baseline. Eighteen patients(72%) had newly diagnosed disease upon study entry (13 patients with GPA and 5 patients with MPA)and 7 patients had relapsing disease (6 patients with GPA and 1 patient with MPA).

The study design consisted of an initial 6-month remission induction phase, with a minimum 18-month follow-up, up to a maximum of 54 months (4.5 years) overall. Patients were to receive aminimum of 3 doses of intravenous methylprednisolone (30 mg/kg/day, not exceeding 1 g/day) priorto the first rituximab intravenous infusion. If clinically indicated, additional daily doses (up to three),of intravenous methylprednisolone could be given. The remission induction regimen consisted of fouronce weekly intravenous infusions of rituximab at a dose of 375 mg/m2 BSA, on study days 1, 8, 15and 22 in combination with oral prednisolone or prednisone at 1 mg/kg/day (max 60 mg/day) taperedto 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, receive subsequent rituximab infusions on or after

Month 6 to maintain PVAS remission and control disease activity (including progressive disease orflare) or to achieve first remission.

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

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

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

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

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

Follow-up treatment

During the Overall Study Period, patients received between 4 and 28 infusions of rituximab (up to 4.5yrs [53.8 months]). Patients received up to 375 mg/m2 x 4 of rituximab, 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 receivedadditional rituximab treatment between Month 6 and Month 18.

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

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

Month 1 0 0.0%, 13.7%

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

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

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

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

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

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

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

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

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

Clinical experience in pemphigus vulgaris

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

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

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

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

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

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

Rituximab + Prednisone

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

N=38

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

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

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

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

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

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

Week 24.

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

The study demonstrated the superiority of rituximab over MMF in combination with a tapering courseof oral corticosteroids in achieving CR off corticosteroid ≥ 16 weeks at Week 52 in PV patients (Table23).The majority of patients in the mITT population were newly diagnosed (74%) and 26% of patientshad established disease (duration of illness ≥ 6 months and received prior treatment for PV).

Table 23 Percentage of PV patients who achieved sustained complete remission offcorticosteroid therapy for 16 weeks or more at week 52 (modified intent-to-treatpopulation)

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

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

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

Patients with established disease

MMF = Mycophenolate mofetil. CI = Confidence Interval.

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

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

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

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

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

Testing of secondary endpoints were controlled for multiplicity.

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

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

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

ADA on safety or efficacy in PV Study 2.

Adult Non-Hodgkin’s lymphoma

Based on a population pharmacokinetic analysis in 298 NHL patients who received single ormultiple infusions of rituximab as a single agent or in combination with CHOP therapy (appliedrituximab doses ranged from 100 to 500 mg/m2), the typical population estimates of nonspecificclearance (CL1), specific clearance (CL2) likely contributed by B cells or tumour burden, andcentral compartment volume of distribution (V1) were 0.14 L/day, 0.59 L/day, and 2.7 L,respectively. The estimated median terminal elimination half-life of rituximab was 22 days (range,6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumour lesionscontributed to some of the variability in CL2 of rituximab in data from 161 patients given375 mg/m2 as an intravenous infusion for 4 weekly doses. Patients with higher CD19-positive cellcounts or tumour lesions had a higher CL2. However, a large component of inter-individualvariability remained for CL2 after correction for CD19-positive cell counts and tumour lesion size.

V1 varied by body surface area (BSA) and CHOP therapy. 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, wererelatively small. Age, gender and WHO performance status had no effect on the pharmacokinetics ofrituximab. This analysis suggests that dose adjustment of rituximab with any of the tested covariatesis not expected to result in a meaningful reduction in its pharmacokinetic variability.

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

Upon administration of rituximab at a dose of 375 mg/m2 as an intravenous infusion at weeklyintervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successiveinfusion, spanning from a mean of 243 µg/mL (range, 16 - 582 µg/mL) after the first infusion to550 µg/mL (range, 171 - 1177 µg/mL) after the eighth infusion.

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

In the clinical trial studying paediatric DLBCL/BL/BAL/BLL, the PK was studied in a subset of 35patients aged 3 years and older. The PK was comparable between the two age groups (≥ 3 to < 12years vs. ε12 to < 8 years). After two rituximab intravenous infusions of 375 mg/m2 in each of the twoinduction cycles (cycle 1 and 2) followed by one rituximab intravenous infusion of 375 mg/m2 in eachof the consolidation cycles (cycle 3 and 4) the maximum concentration was highest after the fourthinfusion (cycle 2) with a geometric mean of 347 µg/mL followed by lower geometric mean maximumconcentrations 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, after2 cycles) and 58.5 µg/mL (pre-dose Cycle 4, after 3 cycles)). The median elimination half-life inpaediatric patients aged 3 years and older was 26 days.

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

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

Table 24: Predicted PK parameters following the rituximab dosing regimen in paediatric

DLBCL/BL/BAL/BLL

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

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

AUC1-4 cycles(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

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

Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the meanterminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day(range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 L (range, 1.7 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 largervolume of distribution and a faster clearance than female subjects. The gender-relatedpharmacokinetic differences are not considered to be clinically relevant and dose adjustment is notrequired. No pharmacokinetic data are available in patients with hepatic or renal impairment.

The pharmacokinetics of rituximab were assessed following two intravenous doses of 500 mg and1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics weredose proportional over the limited dose range studied. Mean Cmax for serum rituximab following firstinfusion ranged from 157 to 171 μg/mL for 2 × 500 mg dose and ranged from 298 to 341 μg/mL for2 × 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 μg/mL for the 2 ×500 mg dose and ranged from 355 to 404 μg/mL for the 2 × 1000 mg dose. Mean terminalelimination half-life ranged from 15 to 16 days for the 2 × 500 mg dose group and 17 to 21 days forthe 2 × 1000 mg dose group. Mean Cmax was 16 to 19% higher following second infusion comparedto the first infusion for both doses.

The pharmacokinetics of rituximab were assessed following two intravenous doses of 500 mg and1000 mg upon re-treatment in the second course. Mean Cmax for serum rituximab following firstinfusion was 170 to 175 μg/mL for 2 × 500 mg dose and 317 to 370 μg/mL for 2 × 1000 mg dose.

Cmax following second infusion, was 207 μg/mL for the 2 × 500 mg dose and ranged from 377 to386 μg/mL for the 2 × 1000 mg dose. Mean terminal elimination half-life after the second infusion,following the second course, was 19 days for 2 × 500 mg dose and ranged from 21 to 22 days for the2 × 1000 mg dose. PK parameters 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 × 1000 mg, intravenous, 2 weeks apart), were similar with a mean maximumserum concentration of 369 μg/mL and a mean terminal half-life of 19.2 days.

Adult Population

Based on the population pharmacokinetic analysis of data in 97 patients with granulomatosis withpolyangiitis and microscopic polyangiitis who received 375 mg/m2 rituximab once weekly for 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 to0.726 L/day) and 4.50 L (range 2.25 to 7.39 L) respectively. Maximum concentration during the first180 days (Cmax), minimum concentration at Day 180 (C180) and Cumulative area under the curveover 180 days (AUC180) were (median [range]) 372.6 (252.3-533.5) µg/mL, 2.1 (0-29.3) µg/mL and10302 (3653-21874) µg/mL*days, respectively. The PK parameters of rituximab in adult GPA and

MPA patients 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 rituximab once weekly for four doses, the estimated median terminalelimination half-life was 22 days (range, 11 to 42 days). Rituximab mean clearance and volume ofdistribution were 0.221 L/day (range, 0. 0996 to 0.381 L/day) and 2.27 L (range 1.43 to 3.17 L)respectively. Maximum concentration during the first 180 days (Cmax), minimum concentration at 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

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

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

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

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

Day 1 and Day 15 Day 168 and Day 182

N=67 N=67

Terminal half-life (days)

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

Clearance (L/day)

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

Central volume of distribution(L) 3.52 3.52

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

Following the first two rituximab administrations (at day 1 and 15, corresponding to cycle 1), the PKparameters of rituximab in patients with PV were similar to those in patients with GPA/MPA 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 depletionof B cells in peripheral blood and in lymphoid tissue.

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to thefoetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in thelymphoid organs of the foetuses was observed, which persisted post natally and was accompaniedby a decrease in IgG level in the newborn animals affected. B cell counts returned to normal in theseanimals within 6 months of birth and did not compromise the reaction to immunisation.

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

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

Sodium chloride

Tri-sodium citrate dihydrate (E331)

Polysorbate 80 (E433)

Water for injections

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

Unopened vial4 years

Diluted product

The prepared infusion solution of rituximab in 0.9% sodium chloride solution is physicallyand chemically stable for 30 days at 2 °C - 8 °C and subsequently 24 hours at roomtemperature (not more than 30 °C).

The prepared infusion solution of rituximab in 5% glucose solution is physically andchemically stable for 24 hours at 2 °C - 8 °C and subsequently 12 hours at room temperature(not more than 30 °C).

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

Store in a refrigerator (2 °C - 8 °C). Keep the vial in the outer carton in order to protect from light.

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

Blitzima 100 mg concentrate for solution for infusion

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

Blitzima 500 mg concentrate for solution for infusion

Clear Type I glass vial with butyl rubber stopper containing 500 mg of rituximab in 50 mL. Pack of 1vial.

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

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

Blitzima, 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 beobserved. Parenteral medicinal products should beinspected visually for particulate matter and discolouration prior to administration.

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

Celltrion Healthcare Hungary Kft.1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

Blitzima 100 mg concentrate for solution for infusion

EU/1/17/1205/002

Blitzima 500 mg concentrate for solution for infusion

EU/1/17/1205/001

Date of first authorisation: 13 July 2017

Date of latest renewal: 25 April 2022

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

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