MabThera

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 

  



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1. NAME OF THE MEDICINAL PRODUCT 
 
MabThera 100 mg concentrate for solution for infusion 
MabThera 500 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
MabThera 100 mg concentrate for solution for infusion 
Each mL contains 10 mg of rituximab. 
Each 10 mL vial contains 100 mg of rituximab. 
 
MabThera 500 mg concentrate for solution for infusion  
Each mL contains 10 mg of rituximab.  
Each 50 mL vial contains 500 mg of rituximab. 
 
Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a 
glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and 
heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster 
ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including 
specific viral inactivation and removal procedures. 
 
Excipients with known effects 
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. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
 
Clear, colourless liquid with pH of 6.2 – 6.8 and osmolality of 324 - 396 mOsmol/kg . 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
MabThera is indicated in adults for the following indications: 
 
Non-Hodgkin’s lymphoma (NHL) 
 
MabThera is indicated for the treatment of previously untreated adult patients with stage III-IV 
follicular lymphoma in combination with chemotherapy.  
 
MabThera maintenance therapy is indicated for the treatment of adult follicular lymphoma patients 
responding to induction therapy.  
 
MabThera monotherapy is indicated for treatment of adult patients with stage III-IV follicular 
lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.  
 
MabThera is indicated for the treatment of adult patients with CD20 positive diffuse large B cell 
non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, 
prednisolone) chemotherapy.  



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MabThera 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 diffuse 
large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL)/Burkitt leukaemia (mature B-cell acute 
leukaemia) (BAL) or Burkitt-like lymphoma (BLL).  
 
Chronic lymphocytic leukaemia (CLL) 
 
MabThera in combination with chemotherapy is indicated for the treatment of patients with previously 
untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for 
patients previously treated with monoclonal antibodies including MabThera or patients refractory to 
previous MabThera plus chemotherapy. 
 
See section 5.1 for further information. 
 
Rheumatoid arthritis 
 
MabThera in combination with methotrexate is indicated for the treatment of adult patients with severe 
active rheumatoid arthritis who have had an inadequate response or intolerance to other 
disease-modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor 
(TNF) inhibitor therapies. 
 
MabThera has been shown to reduce the rate of progression of joint damage as measured by X-ray and 
to improve physical function, when given in combination with methotrexate. 
 
Granulomatosis with polyangiitis and microscopic polyangiitis  
 
MabThera, in combination with glucocorticoids, is indicated for the treatment of adult patients with 
severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis 
(MPA). 
 
MabThera, in combination with glucocorticoids, is indicated for the induction of remission in 
paediatric patients (aged ≥ 2 to < 18 years old) with severe, active GPA (Wegener’s) and MPA. 
 
Pemphigus vulgaris 
 
MabThera is indicated for the treatment of patients with moderate to severe pemphigus vulgaris (PV). 
 
4.2 Posology and method of administration 
 
MabThera should be administered under the close supervision of an experienced healthcare 
professional, and in an environment where full resuscitation facilities are immediately available (see 
section 4.4). 
 
Premedication and prophylactic medications 
 
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and 
diphenhydramine, should always be given before each administration of MabThera. 
 
In adult patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should 
be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy.  
 
In paediatric patients with non Hodgkin’s lymphoma, premedication with paracetamol and H1 
antihistamine (= diphenhydramine or equivalent) should be administered 30 to 60 minutes before the 
start of the infusion of MabThera. In addition, prednisone should be given as indicated in Table 1. 
 



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Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start 
of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL 
patients whose lymphocyte counts are > 25 x 109/L it is recommended to administer 
prednisone/prednisolone 100 mg intravenous shortly before infusion with MabThera to decrease the 
rate and severity of acute infusion reactions and/or cytokine release syndrome. 
 
In patients with rheumatoid arthritis, GPA or MPA or pemphigus vulgaris, premedication with 100 mg 
intravenous methylprednisolone should be completed 30 minutes prior to each infusion of MabThera 
to decrease the incidence and severity of infusion related reactions (IRRs). 
 
In adult patients with GPA or MPA, methylprednisolone given intravenously for 1 to 3 days at a dose 
of 1000 mg per day is recommended prior to the first infusion of MabThera (the last dose of 
methylprednisolone may be given on the same day as the first infusion of MabThera).  This should be 
followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible 
based on clinical need) during and after the 4 week induction course of MabThera treatment.  
 
Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for adult patients with 
GPA/MPA or PV during and following MabThera treatment, as appropriate according to local clinical 
practice guidelines. 
 
Paediatric population 
In paediatric patients with GPA or MPA, prior to the first MabThera IV infusion, methylprednisolone 
should be given IV for three daily doses of 30 mg/kg/day (not to exceed 1 g/day) to treat severe 
vasculitis symptoms. Up to three additional daily doses of 30 mg/kg IV methylprednisolone can be 
given prior to the first MabThera infusion. 
 
Following completion of IV methylprednisolone administration, patients should receive oral 
prednisone 1 mg/kg/day (not to exceed 60 mg/day) and tapered as rapidly as possible per clinical need 
(see section 5.1). 
 
Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for paediatric patients with 
GPA or MPA during and following MabThera treatment, as appropriate. 
 
Posology 
 
It is important to check the medicinal product labels to ensure that the appropriate formulation 
(intravenous or subcutaneous formulation) is being given to the patient, as prescribed. 
 
Non-Hodgkin’s lymphoma 
 
Follicular non-Hodgkin's lymphoma 
 
Combination therapy 
The recommended dose of MabThera in combination with chemotherapy for induction treatment of 
previously untreated or relapsed/refractory patients with follicular lymphoma is: 375 mg/m2 body 
surface area per cycle, for up to 8 cycles. 
 
MabThera should be administered on day 1 of each chemotherapy cycle, after intravenous 
administration of the glucocorticoid component of the chemotherapy if applicable. 
 
Maintenance therapy 

• Previously untreated follicular lymphoma 
The recommended dose of MabThera used as a maintenance treatment for patients with previously 
untreated follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface 
area once every 2 months (starting 2 months after the last dose of induction therapy) until disease 
progression or for a maximum period of two years (12 infusions in total). 
 



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• Relapsed/refractory follicular lymphoma 
The recommended dose of MabThera used as a maintenance treatment for patients with 
relapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m2 
body surface area once every 3 months (starting 3 months after the last dose of induction therapy) until 
disease progression or for a maximum period of two years (8 infusions in total). 
 
Monotherapy 

• Relapsed/refractory follicular lymphoma 
The recommended dose of MabThera monotherapy used as induction treatment for adult patients with 
stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse 
after chemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once 
weekly for four weeks.  
 
For retreatment with MabThera monotherapy for patients who have responded to previous treatment 
with MabThera monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is: 
375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks 
(see section 5.1).  
 
Adult Diffuse large B cell non-Hodgkin's lymphoma 
 
MabThera should be used in combination with CHOP chemotherapy. The recommended dosage is 
375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after 
intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of MabThera 
have not been established in combination with other chemotherapies in diffuse large B cell 
non-Hodgkin’s lymphoma. 
 
Dose adjustments during treatment 
 
No dose reductions of MabThera are recommended. When MabThera is given in combination with 
chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be 
applied. 
 
Chronic lymphocytic leukaemia 
 
The recommended dosage of MabThera in combination with chemotherapy for previously untreated 
and relapsed/refractory patients is 375 mg/m2 body surface area administered on day 0 of the first 
treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent 
cycle for 6 cycles in total. The chemotherapy should be given after MabThera infusion. 
 
Rheumatoid arthritis 
 
Patients treated with MabThera must be given the patient alert card with each infusion. 
 
A course of MabThera consists of two 1000 mg intravenous infusions. The recommended dosage of 
MabThera is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion 
two weeks later. 
 
The need for further courses should be evaluated 24 weeks following the previous course. Retreatment 
should be given at that time if residual disease activity remains, otherwise retreatment should be 
delayed until disease activity returns. 
 
Available data suggest that clinical response is usually achieved within 16 - 24 weeks of an initial 
treatment course. Continued therapy should be carefully reconsidered in patients who show no 
evidence of therapeutic benefit within this time period. 
 



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Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 
 
Patients treated with MabThera must be given the patient alert card with each infusion.  
 
Adult induction of remission 
The recommended dosage of MabThera for induction of remission therapy  in adult patients with GPA 
and MPA is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 
weeks (four infusions in total).  
 
Adult maintenance treatment 
Following induction of remission with MabThera, maintenance treatment in adult patients with GPA 
and MPA should be initiated no sooner than 16 weeks after the last MabThera infusion. 
 
Following induction of remission with other standard of care immunosuppressants, MabThera 
maintenance treatment should be initiated during the 4 week period that follows disease remission.  
 
MabThera should be administered as two 500 mg IV infusions separated by two weeks, followed by a 
500 mg IV infusion every 6 months thereafter. Patients should receive MabThera for at least 24 
months after achievement of remission (absence of clinical signs and symptoms).  For patients who 
may be at higher risk for relapse, physicians should consider a longer duration of MabThera 
maintenance therapy, up to 5 years.  
 
Pemphigus vulgaris 
 
Patients treated with MabThera must be given the patient alert card with each infusion. 
 
The recommended dosage of MabThera for the treatment of pemphigus vulgaris is 1000 mg 
administered as an IV infusion followed two weeks later by a second 1000 mg IV infusion in 
combination with a tapering course of glucocorticoids. 
 
Maintenance treatment 
A maintenance infusion of 500 mg IV should be administered at months 12 and 18, and then every 6 
months thereafter if needed, based on clinical evaluation. 
 
Treatment of relapse 
In the event of relapse, patients may receive 1000 mg IV.  The healthcare provider should also 
consider resuming or increasing the patient’s glucocorticoid dose based on clinical evaluation.  
 
Subsequent infusions may be administered no sooner than 16 weeks following the previous infusion. 
 
Special populations 
 
Paediatric population 
 
Non-Hodgkin’s lymphoma 
 
In paediatric patients from ≥ 6 months to < 18 years of age with previously untreated, advanced stage 
CD20 positive DLBCL/BL/BAL/BLL, MabThera should be used in combination with systemic 
Lymphome Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dosage of 
MabThera is 375mg/m2 BSA, administered as an IV infusion. No MabThera dose adjustments, other 
than by BSA, are required. 
 
The safety and efficacy of MabThera paediatric patients ≥ 6 months to < 18 years of age has not been 
established in indications other than previously untreated advanced stage CD20 positive 
DLBCL/BL/BAL/BLL. Only limited data are available for patients under 3 years of age. See section 
5.1 for further information.  
 



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MabThera should not be used in paediatric patients from birth to < 6 months of age with CD20 
positive diffuse large B-cell lymphoma (see section 5.1) 
 
Table 1 Posology of MabThera administration for Non-Hodgkin’s lymphoma paediatric 

patients 
Cycle Day of treatment Administration details 

Prephase (COP) No MabThera given - 

Induction course 1 
(COPDAM1) 

Day -2 
(corresponding to day 6 
of the prephase) 
1st MabThera infusion 

 
During the 1st induction course, prednisone is 
given as part of the chemotherapy course, and 
should be administered prior to MabThera. 

Day 1 
2nd MabThera infusion 

 
MabThera will be given 48 hours after thefirst 
infusion of MabThera. 

Induction course 2 
(COPDAM2) 

Day -2 
3rd MabThera infusion 

 
In the 2nd induction course, prednisone is not 
given at the time of MabThera administration. 

Day 1 
4th MabThera infusion 

 
MabThera will be given 48 hours after the third 
infusion of MabThera. 

Consolidation 
course 1 
(CYM/CYVE) 

Day 1 
5th MabThera infusion 

 
Prednisone is not given at the time of MabThera 
administration. 

Consolidation 
course 2 
(CYM/CYVE) 

Day 1 
6th MabThera infusion 

 
Prednisone is not given at the time of MabThera 
administration. 

Maintenance 
course 1 (M1) 

Day 25 to 28 of 
consolidation course 2 
(CYVE) 
No MabThera given 

 
Starts when peripheral counts have recovered 
from consolidation course 2 (CYVE) with ANC> 
1.0 x 109/l and platelets > 100 x 109/l  

Maintenance 
course 2 (M2) 

Day 28 of maintenance 
course 1 (M1) 
No MabThera given 

- 

ANC = Absolute Neutrophil Count; COP = Cyclophosphamide, Vincristine, Prednisone; COPDAM = Cyclophosphamide, 
Vincristine, Prednisolone, Doxorubicin, Methotrexate; CYM = CYtarabine (Aracytine, Ara-C), Methotrexate; CYVE = 
CYtarabine (Aracytine, Ara-C), VEposide (VP16)  

 



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Table 2 Treatment Plan for Non-Hodgkin’s lymphoma paediatric patients: Concomitant 
Chemotherapy with MabThera  

Treatment 
Plan 

Patient Staging Administration details 

Group B Stage III with high LDH level (> N x 
2), 
Stage IV CNS negative 

Prephase followed by 4 courses:  
2 induction courses (COPADM) with 
HDMTX 3g/m2 and 2 consolidation courses 
(CYM)  

Group C Group C1: 
B- AL CNS negative, Stage IV & BAL 
CNS positive and CSF negative 

Prephase followed by 6 courses:  
2 induction courses (COPADM) with 
HDMTX 8g/m², 2 consolidation courses 
(CYVE) and 2 maintenance courses  (M1 
and M2)  

Group C3: 
BAL CSF positive, Stage IV CSF 
positive 

Consecutive courses should be given as soon as blood count recovery and patient’s condition allows 
except for the maintenance courses which are given at 28 day intervals 
BAL = Burkitt leukaemia (mature B-cell acute leukaemia); CSF = Cerebrospinal  Fluid; CNS = Central Nervous System; 
HDMTX = High-dose Methotrexate; LDH = Lactic Acid Dehydrogenase 

 
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 
Induction of remission 
The recommended dosage of MabThera for induction of remission therapy in paediatric patients with 
severe, active GPA or MPA is 375 mg/m2 BSA, administered as an IV infusion once weekly for 4 weeks. 

The safety and efficacy of MabThera in paediatric patients (≥ 2 to < 18 years of age) has not been 
established in indications other than severe, active GPA or MPA. 
MabThera should not be used in paediatric patients less than 2 years of age with severe, active GPA or 
MPA as there is a possibility of an inadequate immune response towards childhood vaccinations 
against common, vaccine preventable childhood diseases (e.g. measles, mumps, rubella, and 
poliomyelitis) (see section 5.1). 
 
Elderly 
No dose adjustment is required in elderly patients (aged >65 years). 
 
Method of administration 
 
The prepared MabThera solution should be administered as an intravenous infusion through a 
dedicated line. It should not be administered as an intravenous push or bolus. 
 
Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). 
Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or 
hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma 
should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests 
and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted 
until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray 
findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. 
If the same severe adverse reactions occur for a second time, the decision to stop the treatment should 
be seriously considered on a case by case basis. 
 
Mild or moderate infusion-related reactions (IRR) (section 4.8) usually respond to a reduction in the 
rate of infusion. The infusion rate may be increased upon improvement of symptoms.  
 



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First infusion 
 
The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 
50 mg/h increments every 30 minutes, to a maximum of 400 mg/h. 
 
Subsequent infusions  
 
All indications 
 
Subsequent doses of MabThera can be infused at an initial rate of 100 mg/h, and increased by 
100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h. 
 
Paediatric patients – non-Hodgkin’s lymphoma 
 
First infusion  
 
The recommended initial rate for infusion is 0.5 mg/kg/h (maximum 50 mg/h); it can be escalated by 
0.5 mg/kg/h every 30 minutes if there is no hypersensitivity or infusion-related reactions, to a 
maximum of 400 mg/h. 
 
Subsequent infusions  
 
Subsequent doses of MabThera can be infused at an initial rate of 1 mg/kg/h (maximum 50 mg/h); it 
can be increased by 1 mg/kg/h every 30 minutes to a maximum of 400 mg/h. 
 
Rheumatoid arthritis only  
 
Alternative subsequent, faster, infusion schedule 
 
If patients did not experience a serious infusion-related reaction with their first or subsequent infusions 
of a dose of 1000 mg MabThera administered over the standard infusion schedule, a more rapid 
infusion can be administered for second and subsequent infusions using the same concentration as in 
previous infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250 mg/hour for the first 30 
minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this 
infusion schedule can be used when administering subsequent infusions. 
 
Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous 
serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the 
more rapid infusion. 
 
4.3 Contraindications 
 
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 in 
section 6.1. 
 
Active, severe infections (see section 4.4). 
 
Patients in a severely immunocompromised state. 
 
Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis, microscopic 
polyangiitis and pemphigus vulgaris 
 
Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in 
section 6.1. 
 



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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). 
 
4.4 Special warnings and precautions for use 
 
Traceability  
In order to improve traceability of biological medicinal products, the tradename and batch number of 
the administered product should be clearly recorded.  
   
Progressive multifocal leukoencephalopathy 
 
All patients treated with MabThera for rheumatoid arthritis, GPA, MPA or pemphigus vulgaris must 
be given the patient alert card with each infusion. The alert card contains important safety information 
for patients regarding potential increased risk of infections, including progressive multifocal 
leukoencephalopathy (PML). 
 
Very rare cases of fatal PML have been reported following use of MabThera. Patients must be 
monitored at regular intervals for any new or worsening neurological symptoms or signs that may be 
suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been 
excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of 
neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. 
Consultation with a Neurologist should be considered as clinically indicated. 
 
If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal 
fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.  
 
The physician should be particularly alert to symptoms suggestive of PML that the patient may not 
notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to 
inform their partner or caregivers about their treatment, since they may notice symptoms that the 
patient is not aware of. 
 
If a patient develops PML, the dosing of MabThera must be permanently discontinued.  
 
Following reconstitution of the immune system in immunocompromised patients with PML, 
stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and 
suspension of MabThera therapy may lead to similar stabilisation or improved outcome. 
 
Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia 
 
Infusion-related reactions 
MabThera is associated with infusion-related reactions, which may be related to release of cytokines 
and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from 
acute hypersensitivity reactions. 
 
This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and 
anaphylactic and hypersensitivity reactions are described below. They are not specifically related to 
the route of administration of MabThera and can be observed with both formulations. 
 
Severe infusion-related reactions with fatal outcome have been reported during post-marketing use of 
the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after 
starting the first MabThera intravenous infusion. They were characterised by pulmonary events and in 
some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, 
chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8). 



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Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by 
bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This 
syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, 
hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate 
dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute 
respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, 
visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating 
the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour 
infiltration may be at greater risk of poor outcome and should be treated with increased caution. 
Patients who develop severe cytokine release syndrome should have their infusion interrupted 
immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial 
improvement of clinical symptoms may be followed by deterioration, these patients should be closely 
monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. 
Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in 
repeated severe cytokine release syndrome. 
 
Patients with a high tumour burden or with a high number (≥25 x 109/L) of circulating malignant cells 
such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome, 
should be treated with extreme caution. These patients should be very closely monitored throughout 
the first infusion. Consideration should be given to the use of a reduced infusion rate for the first 
infusion in these patients or a split dosing over two days during the first cycle and any subsequent 
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 with 
MabThera (including cytokine release syndrome accompanied by hypotension and bronchospasm in 
10% of patients) see section 4.8. These symptoms are usually reversible with interruption of 
MabThera infusion and administration of an anti-pyretic, an antihistaminic and occasionally oxygen, 
intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine release 
syndrome above for severe reactions. 
 
Anaphylactic and other hypersensitivity reactions have been reported following the intravenous 
administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity 
reactions typically occur within minutes after starting infusion. 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 allergic reaction during administration of MabThera. 
Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine 
release syndrome (described above). Reactions attributed to hypersensitivity have been reported less 
frequently than those attributed to cytokine release. 
 
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary 
oedema and acute reversible thrombocytopenia. 
 
Since hypotension may occur during MabThera administration, consideration should be given to 
withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion. 
 
Cardiac disorders 
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or 
myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a 
history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. 
 
Haematological toxicities 
Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when 
considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L as 
clinical experience in this population is limited. MabThera has been used in 21 patients who 
underwent autologous bone marrow transplantation and other risk groups with a presumable reduced 
bone marrow function without inducing myelotoxicity. 



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Regular full blood counts, including neutrophil and platelet counts, should be performed during 
MabThera therapy.  
 
Infections 
Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). 
MabThera 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 MabThera in patients with a history of 
recurring or chronic infections or with underlying conditions which may further predispose patients to 
serious infection (see section 4.8).  
 
Cases of hepatitis B reactivation have been reported in subjects receiving MabThera including 
fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic 
chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that 
MabThera 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 MabThera. At 
minimum this should include HBsAg-status and HBcAb-status. These can be complemented with 
other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be 
treated with MabThera. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should 
consult liver disease experts before start of treatment and should be monitored and managed following 
local medical standards to prevent hepatitis B reactivation. 
 
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during 
post-marketing use of MabThera in NHL and CLL (see section 4.8). The majority of patients had 
received MabThera in combination with chemotherapy or as part of a hematopoietic stem cell 
transplant.  
 
Immunisations 
The safety of immunisation with live viral vaccines, following MabThera therapy has not been studied 
for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients 
treated with MabThera may receive non-live vaccinations; however, with non-live vaccines response 
rates may be reduced. In a non-randomised study, adult patients with relapsed low-grade NHL who 
received MabThera monotherapy when compared to healthy untreated controls had a lower rate of 
response 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 but that has not 
been investigated in clinical trials. 
 
Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza 
A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with MabThera.  
 
Skin reactions 
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). In case of such an event, 
with a suspected relationship to MabThera, treatment should be permanently discontinued.  
 
Paediatric population 
Only limited data are available for patients under 3 years of age. See section 5.1 for further 
information. 
 



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Rheumatoid arthritis, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), 
and pemphigus vulgaris 
 
Methotrexate (MTX) naïve populations with rheumatoid arthritis 
The use of MabThera is not recommended in MTX-naïve patients since a favourable benefit risk 
relationship has not been established. 
 
Infusion-related reactions 
MabThera is associated with infusion related reactions (IRRs), which may be related to release of 
cytokines and/or other chemical mediators.  
 
Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the 
post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials 
were mild to moderate in severity. The most common symptoms were allergic reactions like headache, 
pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion 
of patients experiencing any infusion reaction was higher following the first infusion than following 
the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses 
(see section 4.8). The reactions reported were usually reversible with a reduction in rate, or 
interruption, of MabThera infusion and administration of an anti-pyretic, an antihistamine, and, 
occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely 
monitor patients with pre-existing cardiac conditions and those who experienced prior 
cardiopulmonary adverse reactions. Depending on the severity of the IRR and the required 
interventions, temporarily or permanently discontinue MabThera. In most cases, the infusion can be 
resumed at a 50% reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely 
resolved. 
 
Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline), 
antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic 
reaction during administration of MabThera.  
 
There are no data on the safety of MabThera in patients with moderate heart failure (NYHA class III) 
or severe, uncontrolled cardiovascular disease. In patients treated with MabThera, the occurrence of 
pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been 
observed, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history, 
and those who experienced prior cardiopulmonary adverse reactions, the risk of cardiovascular 
complications resulting from infusion reactions should be considered before treatment with MabThera 
and patients closely monitored during administration. Since hypotension may occur during MabThera 
infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to 
the MabThera infusion. 
 
IRRs in patients with GPA, MPA and pemphigus vulgaris were consistent with those seen for 
rheumatoid arthritis patients in clinical trials and in the post-marketing setting (see section 4.8). 
 
Cardiac disorders 
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or 
myocardial infarction have occurred in patients treated with MabThera. Therefore, patients with a 
history of cardiac disease should be monitored closely (see Infusion-related reactions, above). 
 



14 

Infections 
Based on the mechanism of action of MabThera and the knowledge that B cells play an important role 
in maintaining normal immune response, patients have an increased risk of infection following 
MabThera therapy (see section 5.1). Serious infections, including fatalities, can occur during therapy 
with MabThera (see section 4.8). MabThera should not be administered to patients with an active, 
severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely 
immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should 
exercise caution when considering the use of MabThera in patients with a history of recurring or 
chronic infections or with underlying conditions which may further predispose patients to serious 
infection, e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulin 
levels are determined prior to initiating treatment with MabThera. 
 
Patients reporting signs and symptoms of infection following MabThera therapy should be promptly 
evaluated and treated appropriately. Before giving a subsequent course of MabThera treatment, 
patients should be re-evaluated for any potential risk for infections. 
 
Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported 
following use of MabThera for the treatment of rheumatoid arthritis and autoimmune diseases 
including Systemic Lupus Erythematosus (SLE) and vasculitis. 
 
Hepatitis B Infections 
Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in 
rheumatoid arthritis, GPA and MPA patients receiving MabThera. 
 
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment 
with MabThera. At minimum this should include HBsAg-status and HBcAb-status. These can be 
complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B 
disease should not be treated with MabThera. Patients with positive hepatitis B serology (either 
HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be 
monitored and managed following local medical standards to prevent hepatitis B reactivation. 
 
Late neutropenia 
Measure blood neutrophils prior to each course of MabThera, and regularly up to 6-months after 
cessation of treatment, and upon signs or symptoms of infection (see section 4.8).  
 
Skin reactions 
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). In case of such an event 
with a suspected relationship to MabThera, treatment should be permanently discontinued.  
 
Immunisation 
Physicians should review the patient’s vaccination status and  patients should, if possible, be brought 
up-to-date with all immunisations in agreement with current immunisation guidelines prior to 
initiating MabThera therapy. Vaccination should be completed at least 4 weeks prior to first 
administration of MabThera. 
 
The safety of immunisation with live viral vaccines following MabThera therapy has not been studied. 
Therefore vaccination with live virus vaccines is not recommended whilst on MabThera or whilst 
peripherally B cell depleted.  
 
Patients treated with MabThera may receive non-live vaccinations; however, response rates to 
non-live vaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated with 
MabThera and methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%), 
reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal 
antibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after MabThera as 
compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst 



15 

receiving MabThera therapy, these should be completed at least 4 weeks prior to commencing the next 
course of MabThera.  
 
In the overall experience of MabThera repeat treatment over one year in rheumatoid arthritis, the 
proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, 
varicella and tetanus toxoid were generally similar to the proportions at baseline.  
 
Concomitant/sequential use of other DMARDs in rheumatoid arthritis 
The concomitant use of MabThera and anti-rheumatic therapies other than those specified under the 
rheumatoid arthritis indication and posology is not recommended. 
 
There are limited data from clinical trials to fully assess the safety of the sequential use of other 
DMARDs (including TNF inhibitors and other biologics) following MabThera (see section 4.5). The 
available data indicate that the rate of clinically relevant infection is unchanged when such therapies 
are used in patients previously treated with MabThera, however patients should be closely observed 
for signs of infection if biologic agents and/or DMARDs are used following MabThera therapy. 
 
Malignancy 
Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience 
with MabThera in rheumatoid arthritis patients (see section 4.8) the present data do not seem to 
suggest any increased risk of malignancy. However, the possible risk for the development of solid 
tumours cannot be excluded at this time. 
 
Excipients  
This medicinal product contains 2.3 mmol (or 52.6 mg) sodium per 10 mL vial and 11.5 mmol (or 
263.2 mg) sodium per 50 mL vial, equivalent to 2.6% (for 10ml vial) and 13.2% (for 50ml vial) of the 
WHO recommended maximum daily intake of 2 g sodium for an adult.  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Currently, there are limited data on possible drug interactions with MabThera.  
 
In CLL patients, co-administration with MabThera did not appear to have an effect on the 
pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of 
fludarabine and cyclophosphamide on the pharmacokinetics of MabThera. 
 
Co-administration with methotrexate had no effect on the pharmacokinetics of MabThera in 
rheumatoid arthritis patients. 
 
Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have 
allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal 
antibodies. 
 
In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic 
DMARD following MabThera. In these patients the rate of clinically relevant infection while on 
MabThera was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment 
with the biologic DMARD.  
 
4.6 Fertility, pregnancy and lactation 
 
Contraception in males and females 
 
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing 
potential should use effective contraceptive methods during and for 12 months following treatment 
with MabThera. 
 



16 

Pregnancy 
 
IgG immunoglobulins are known to cross the placental barrier. 
 
B cell levels in human neonates following maternal exposure to MabThera have not been studied in 
clinical 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 to 
mothers exposed to MabThera during pregnancy. Similar effects have been observed in animal studies 
(see section 5.3). For these reasons MabThera should not be administered to pregnant women unless 
the possible benefit outweighs the potential risk. 
 
Breast-feeding 
 
Whether rituximab is excreted in human milk is not known. However, because maternal IgG is 
excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should 
not breastfeed while treated with MabThera and for 12 months following MabThera treatment. 
 
Fertility 
 
Animal studies did not reveal deleterious effects of rituximab on reproductive organs.  
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects of MabThera on the ability to drive and use machines have been performed, 
although the pharmacological activity and adverse reactions reported to date suggest that MabThera 
would have no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia in adults 
 
Summary of the safety profile 
 
The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data from 
patients from clinical trials and from post-marketing surveillance. These patients were treated either 
with MabThera monotherapy (as induction treatment or maintenance treatment following induction 
treatment) or in combination with chemotherapy.  
 
The most frequently observed adverse reactions (ADRs) in patients receiving MabThera were IRRs 
which occurred in the majority of patients during the first infusion. The incidence of infusion-related 
symptoms decreases substantially with subsequent infusions and is less than 1% after eight doses of 
MabThera. 
 
Infectious events (predominantly bacterial and viral) occurred in approximately 30-55% of patients 
during clinical trials in patients with NHL and in 30-50% of patients during clinical trials in patients 
with CLL. 
 
The most frequently reported or observed serious adverse reactions were: 
• IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4. 
• Infections, see section 4.4. 
• Cardiovascular events, see section 4.4. 
 
Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.).  
 



17 

Tabulated list of adverse reactions 
 
The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are 
summarised in Table 3. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to 
< 1/10), uncommon (≥  1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) and 
not known (cannot be estimated from the available data). Within each frequency grouping, undesirable 
effects are presented in the order of decreasing seriousness. 
 
The ADRs identified only during post-marketing surveillance, and for which a frequency could not be 
estimated, are listed under “not known”. 
 
Table 3 ADRs reported in clinical trials or during postmarketing surveillance in patients 

with NHL and CLL disease treated with MabThera monotherapy/maintenance or in 
combination with chemotherapy  

MedDRA 

System 
Organ Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

Infections 
and 
infestations 

bacterial 
infections, 
viral 
infections, 
+bronchitis  
 

sepsis, 
+pneumonia, 
+febrile infection, 
+herpes zoster, 
+respiratory tract 
infection, fungal 
infections, 
infections of 
unknown 
aetiology, +acute 
bronchitis, 
+sinusitis, 
hepatitis B1  

 serious viral 
infection2 
Pneumocystis 
jirovecii 

PML  

Blood and 
lymphatic 
system 
disorders 

neutropenia, 
leucopenia, 
+febrile 
neutropenia, 
+thrombocytop
enia 
 

anaemia,  
+pancytopenia, 
+granulocytopenia 

coagulation 
disorders, aplastic 
anaemia, 
haemolytic 
anaemia, 
lymphadenopathy 

 transient 
increase in 
serum IgM 
levels3 

late 
neutropenia
3 

Immune 
system 
disorders 

infusion-
related 
reactions4, 
angioedema 

hypersensitivity  anaphylaxis tumour lysis 
syndrome, 
cytokine release 
syndrome4, 
serum sickness 

infusion-rel
ated acute 
reversible 
thrombocyt
openia4 

Metabolism 
and nutrition 
disorders 

 hyperglycaemia, 
weight decrease, 
peripheral 
oedema, face 
oedema, increased 
LDH, 
hypocalcaemia 

    

Psychiatric 
disorders 

  depression, 
nervousness 

   

Nervous 
system 
disorders 

 paraesthesia, 
hypoaesthesia, 
agitation, 
insomnia, 
vasodilatation, 
dizziness, anxiety 

dysgeusia  peripheral 
neuropathy, 
facial nerve 
palsy5 

cranial 
neuropathy, 
loss of 
other 
senses5 

Eye 
disorders 

 lacrimation 
disorder, 
conjunctivitis 

  severe vision 
loss5 

 

Ear and 
labyrinth 
disorders 

 tinnitus, ear pain    hearing 
loss5 



18 

MedDRA 

System 
Organ Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

Cardiac 
disorders 

 +myocardial 
infarction4 and 6, 
arrhythmia, +atrial 
fibrillation, 
tachycardia, 
+cardiac disorder 

+left ventricular 
failure, 
+supraventricular 
tachycardia,  
+ventricular 
tachycardia,  
+angina,  
+myocardial 
ischaemia, 
bradycardia 

severe cardiac 
disorders 4 and 
6 

heart failure4 and 
6 

 

Vascular 
disorders 

 hypertension, 
orthostatic 
hypotension, 
hypotension  

  vasculitis 
(predominately 
cutaneous), 
leukocytoclastic 
vasculitis 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Bronchospasm4, 
respiratory 
disease, chest 
pain, dyspnoea, 
increased cough, 
rhinitis 

asthma, 
bronchiolitis 
obliterans, lung 
disorder, hypoxia 

interstitial 
lung disease7 

respiratory 
failure4 
 

lung 
infiltration  

Gastrointesti
nal disorders 

nausea  vomiting, 
diarrhoea, 
abdominal pain, 
dysphagia, 
stomatitis, 
constipation, 
dyspepsia, 
anorexia, throat 
irritation 

abdominal 
enlargement 

 gastro-intestinal 
perforation7 

 

Skin and 
subcutaneou
s tissue 
disorders 

pruritus, rash, 
+alopecia  

urticaria, 
sweating, night 
sweats, +skin 
disorder 

  severe bullous 
skin reactions, 
Stevens-Johnson 
syndrome, 
toxic epidermal 
necrolysis 
(Lyell’s 
syndrome) 7  

 

Musculoskel
etal, 
connective 
tissue 
disorders 

 hypertonia, 
myalgia, 
arthralgia, back 
pain, neck pain, 
pain 

    

Renal and 
urinary 
disorders 

    renal failure4  



19 

MedDRA 

System 
Organ Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

General 
disorders 
and 
administrati
on site 
conditions 

fever, chills, 
asthenia, 
headache  

tumour pain, 
flushing, malaise, 
cold syndrome, 
+fatigue, 
+shivering,  
+multi-organ 
failure4 

infusion site pain    

Investigation
s 

decreased IgG 
levels 

     

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with 
"+" where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria) reactions.  Only the highest 
frequency observed in the trials is reported 
1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 
2 see also section infection below  
3 see also section haematologic adverse reactions below 
4 see also section infusionrelated reactions below. Rarely fatal cases reported 
5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera 

therapy 
6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with 

infusion-related reactions 
7 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 MabThera arms compared to control arms: 
haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia. 
 
Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of 
patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one 
to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms 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-related reactions (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 cardiac conditions such 
as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial 
infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine 
release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. 
The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is 
<1% of patients by the eighth cycle of MabThera (containing) treatment.  
 
Description of selected adverse reactions 
 
Infections  
MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreased 
serum immunoglobulins only in a minority of patients.  
 
Localised candida infections as well as Herpes zoster were reported at a higher incidence in the 
MabThera-containing arm of randomised studies. Severe infections were reported in about 4% of 
patients treated with MabThera monotherapy. Higher frequencies of infections overall, including 
grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when 
compared to observation. There was no cumulative toxicity in terms of infections reported over a 
2-year treatment period. In addition, other serious viral infections either new, reactivated or 
exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of 
patients had received MabThera in combination with chemotherapy or as part of a haematopoetic stem 
cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses 



20 

(Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal 
leukoencephalopathy (PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease 
progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, 
have been reported, the majority of which were in patients receiving MabThera in combination with 
cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis 
B infection (reactivation and primary infection) was 2% in R-FC vs 0% FC. Progression of Kaposi’s 
sarcoma has been observed in MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These 
cases occurred in non-approved indications and the majority of patients were HIV positive. 
 
Haematologic adverse reactions  
In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities 
occurred 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 
MabThera maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and 
neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to 
observation. The incidence of thrombocytopenia was low (<1%, grade 3/4) and was not different 
between treatment arms. During the treatment course in studies with MabThera in combination with 
chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), 
neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in 
previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were 
usually reported with higher frequencies when compared to chemotherapy alone. However, the higher 
incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with 
a higher incidence of infections and infestations compared to patients treated with chemotherapy 
alone. Studies in previously untreated and relapsed/refractory CLL have established that in up to 25% 
of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining 
below 1x109/L between day 24 and 42 after the last dose) or occurred with a late onset (defined as 
neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous 
prolonged neutropenia or who recovered prior to day 42) following treatment with MabThera plus FC. 
There were no differences reported for the incidence of anaemia. Some cases of late neutropenia 
occurring more than four weeks after the last infusion of MabThera were reported. In the CLL 
first-line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to 
the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 
thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in 
the FC group.  
 
In studies of MabThera in patients with Waldenstrom’s macroglobulinaemia, transient increases in 
serum IgM levels have been observed following treatment initiation, which may be associated with 
hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline 
level within 4 months. 
 
Cardiovascular adverse reactions 
Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% of 
patients with the most frequently reported events being hypotension and hypertension. Cases of grade 
3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during 
infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders 
was comparable between patients treated with MabThera and observation. Cardiac events were 
reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular 
failure, myocardial ischaemia) in 3% of patients treated with MabThera compared to <1% on 
observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of 
grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia 
and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the 
CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera 
infusion or were associated with predisposing conditions such as fever, infection, acute myocardial 
infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP 
and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart 
failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall 



21 

incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and 
in the relapsed/refractory study (4% R-FC, 4% FC).  
 
Respiratory system 
Cases of interstitial lung disease, some with fatal outcome have been reported. 
 
Neurologic disorders  
During the treatment period (induction treatment phase comprising of R-CHOP for at most eight 
cycles), four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experienced 
thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference 
between the treatment groups in the incidence of other thromboembolic events. In contrast, three 
patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the 
follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low both 
in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC).  
 
Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior 
leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual 
disturbance, headache, seizures and altered mental status, with or without associated hypertension. A 
diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised 
risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, 
immunosuppressive therapy and/or chemotherapy. 
 
Gastrointestinal disorders 
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving 
MabThera for treatment of non-Hodgkin lymphoma. In the majority of these cases, MabThera was 
administered with chemotherapy. 
 
IgG levels 
In the clinical trial evaluating MabThera maintenance treatment in relapsed/refractory follicular 
lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction 
treatment in both the observation and the MabThera groups. In the observation group, the median IgG 
level subsequently increased to above the LLN, but remained constant in the MabThera group. The 
proportion of patients with IgG levels below the LLN was about 60% in the MabThera group 
throughout the 2 year treatment period, while it decreased in the observation group (36% after 
2 years). 
 
A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed 
in paediatric patients treated with MabThera, in some cases severe and requiring long-term 
immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric 
patients are unknown. 
 
Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell syndrome) and Stevens-Johnson syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Patient subpopulations - MabThera monotherapy 
Elderly (≥ 65 years):  
The incidence of ADRs of all grades and grade 3/4 ADR was similar in elderly patients compared to 
younger patients (<65 years).  
 
Bulky disease  
There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients 
without bulky disease (25.6% vs. 15.4%). The incidence of ADRs of any grade was similar in these 
two groups. 
 



22 

Re-treatment 
The percentage of patients reporting ADRs upon re-treatment with further courses of MabThera was 
similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 
ADRs). 
 
Patient subpopulations - MabThera combination therapy 
Elderly (≥ 65 years)  
The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients 
compared to younger patients (<65 years), with previously untreated or relapsed/refractory CLL. 
 
Experience from paediatric DLBCL/BL/BAL/BLL 
 
Summary of safety profile 
 
A multicenter, open-label randomized study of Lymphome Malin B chemotherapy (LMB) with or 
without MabThera was conducted in paediatric patients (aged ≥ 6 months to < 18 years old) with 
previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL.  
 
A total of 309 paediatric patients received MabThera and were included in the safety analysis 
population. Paediatric patients randomized to the LMB chemotherapy arm with MabThera, or enrolled 
in the single arm part of the study, were administered MabThera at a dose of 375mg/m2 BSA and 
received a total of six IV infusions of MabThera (two during each of the two induction courses and 
one during each of the two consolidation courses of the LMB  scheme).  
 
The safety profile of MabThera in paediatric patients (aged ≥ 6 months to < 18 years old) with 
previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL was generally consistent in 
type, nature and severity with the known safety profile in adult NHL and CLL patients.    Addition of 
MabThera to chemotherapy did result in an increased risk of some events including infections 
(including sepsis) compared to chemotherapy only.   
 
Experience from rheumatoid arthritis  
 
Summary of the safety profile 
 
The overall safety profile of MabThera in rheumatoid arthritis is based on data from patients from 
clinical trials and from post-marketing surveillance. 
 
The safety profile of MabThera in patients with moderate to severe rheumatoid arthritis (RA) is 
summarised in the sections below. In clinical trials more than 3100 patients received at least one 
treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 
2400 patients received two or more courses of treatment with over 1000 having received 5 or more 
courses. The safety information collected during post marketing experience reflects the expected 
adverse reaction profile as seen in clinical trials for MabThera (see section 4.4).  
 
Patients received 2 x 1000 mg of MabThera separated by an interval of two weeks; in addition to 
methotrexate (10-25 mg/week). MabThera infusions were administered after an intravenous infusion 
of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days. 
 
Tabulated list of adverse reactions 
 
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), and very rare (<1/10,000). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 
The most frequent adverse reactions considered due to receipt of MabThera were IRRs. The overall 
incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent 
infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during the 



23 

initial course.  In addition to adverse reactions seen in RA clinical trials for MabThera, progressive 
multifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like reaction have been 
reported during post marketing experience. 
 
Table 4 Summary of adverse reactions reported in clinical trials or during postmarketing 

surveillance occurring in patients with rheumatoid arthritis receiving MabThera  
MedDRA 

System Organ Class Very Common Common 
Uncommon Rare Very rare 

Infections and 
infestations 

upper respiratory 
tract infection, 
urinary tract 
infections 

bronchitis, sinusitis, 
gastroenteritis, tinea 
pedispedís 

  PML, 
reactivation of 
hepatitis B 

Blood and lymphatic 
system disorders 

 neutropenia1  late 
neutropenia2 

serum 
sickness-like 
reaction 

Immune system 
disorders 

3infusion-related 
reactions 
(hypertension, 
nausea, rash, 
pyrexia, pruritus, 
urticaria, throat 
irritation, hot flush,  
hypotension, 
rhinitis, rigors, 
tachycardia, fatigue, 
oropharyngeal pain, 
peripheral oedema, 
erythema) 

 3infusion related 
reactions 
(generalized 
oedema, 
bronchospasm, 
wheezing, 
laryngeal oedema, 
angioneurotic 
oedema, 
generalized 
pruritus, 
anaphylaxis, 
anaphylactoid 
reaction) 

  

General disorders 
and administration 
site conditions 

Metabolism and 
nutrition disorders 

 Hypercholesterolem
ia 

   

Psychiatric disorders  depression, anxiety    
Nervous system 
disorders 

headache paraesthesia, 
migraine, dizziness, 
sciatica 

   

Cardiac disorders    angina 
pectoris, atrial 
fibrillation, 
heart failure, 
myocardial 
infarction 

atrial flutter 

Gastrointestinal 
disorders 

 dyspepsia, 
diarrhoea, 
gastro-oesophageal 
reflux, mouth 
ulceration, upper 
abdominal pain 

   

Skin and 
subcutaneous tissue 
disorders 

 alopecia   toxic epidermal 
necrolysis 
(Lyell’s 
syndrome), 
Stevens-Johnson 
syndrome5 

Musculo skeletal 
disorders and 
connective tissue 
disorders 

 arthralgia / 
musculoskeletal 
pain, osteoarthritis, 
bursitis 

   

Investigations decreased IgM 
levels4 

decreased IgG 
levels4 

   

1 Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials 
2 Frequency category derived from post-marketing data. 
3 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. 
4 Includes observations collected as part of routine laboratory monitoring. 
5 Includes fatal cases 

 



24 

Multiple courses 
Multiple courses of treatment are associated with a similar ADR profile to that observed following 
first exposure. The rate of all ADRs following first MabThera exposure was highest during the first 6 
months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the first 
treatment course), RA exacerbation and infections, all of which were more frequent in the first 6 
months of treatment.  
 
Description of selected adverse reactions 
 
Infusion-related reactions 
The most frequent ADRs following receipt of MabThera in clinical studies were IRRs (refer to 
Table 4). Among the 3189 patients treated with MabThera, 1135 (36%) experienced at least one IRR 
with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to 
MabThera. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1% 
(17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due 
to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal 
decreased by course and were rare from course 3 onwards. Premedication with intravenous 
glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). 
Severe IRRs with fatal outcome have been reported in the post-marketing setting. 
 
In a trial designed to evaluate the safety of a more rapid MabThera infusion in patients with 
rheumatoid 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-hour intravenous 
infusion of MabThera. Patients with a history of a serious infusion reaction to a biologic therapy for 
RA were excluded from entry. The incidence, types and severity of IRRs were consistent with that 
observed historically.  No serious IRRs were observed. 
 
Infections 
The overall rate of infection was approximately 94 per 100 patient years in MabThera treated patients. 
The infections were predominately mild to moderate and consisted mostly of upper respiratory tract 
infections and urinary tract infections. The incidence of infections that were serious or required IV 
antibiotics was approximately 4 per 100 patient years. The rate of serious infections did not show any 
significant increase following multiple courses of MabThera. Lower respiratory tract infections 
(including pneumonia) have been reported during clinical trials, at a similar incidence in the 
MabThera arms compared to control arms. 
 
Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported following 
use of MabThera for the treatment of autoimmune diseases. This includes rheumatoid arthritis and 
off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and vasculitis. 
 
In patients with non-Hodgkin’s lymphoma receiving MabThera in combination with cytotoxic 
chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma).  
Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving 
MabThera (see Section 4.4). 
 
Cardiovascular adverse reactions 
Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the MabThera treated 
patients compared to 1.3 per 100 patient years in placebo treated patients. The proportions of patients 
experiencing cardiac reactions (all or serious) did not increase over multiple courses. 
 
Neurologic events 
Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior 
leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual 
disturbance, headache, seizures and altered mental status, with or without associated hypertension. A 
diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised 
risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, 
immunosuppressive therapy and/or chemotherapy. 



25 

 
Neutropenia 
Events of neutropenia were observed with MabThera treatment, the majority of which were transient 
and mild or moderate in severity. Neutropenia can occur several months after the administration of 
MabThera (see section 4.4). 
 
In placebo-controlled periods of clinical trials, 0.94% (13/1382) of MabThera treated patients and 
0.27% (2/731) of placebo patients developed severe neutropenia. 
 
Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported 
in the post-marketing setting, some of which were associated with fatal infections. 
 
Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Laboratory abnormalities 
Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA 
patients treated with MabThera. There was no increased rate in overall infections or serious infections 
after the development of low IgG or IgM (see section 4.4).  
 
A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed 
in paediatric patients treated with MabThera, in some cases severe and requiring long-term 
immunoglobulin substitution therapy. The consequences of long-term B cell depletion in paediatric 
patients are unknown. 
 
Experience from granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 
 
Adult induction of remission (GPA/MPA Study 1)  
In GPA/MPA Study 1, 99 adult patients were treated for induction of remission of GPA and MPA 
with MabThera (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 the 
MabThera group and at a higher frequency than the comparator group. 
 
Table 5 Adverse reactions occurring at 6-months in ≥ 5% of adult patients receiving 

MabThera in GPA/MPA Study 1, and at a higher frequency than the comparator 
group. 

MedDRA System organ class 
Adverse reaction 

Rituximab 
(n=99) 

Infections and infestations 
Urinary tract infection 7% 
Bronchitis 5% 
Herpes zoster 5% 
Nasopharyngitis 5% 

Blood and lymphatic 
 system disorder 

Thrombocytopenia 7% 
Immune system disorders 

Cytokine release syndrome 5% 
Metabolism and nutrition disorders 

Hyperkalaemia 5% 
Psychiatric disorders 

Insomnia 14% 



26 

MedDRA System organ class 
Adverse reaction 

Rituximab 
(n=99) 

Nervous system disorders 
Dizziness 10% 
Tremor 10% 

Vascular disorders 
Hypertension 12% 
Flushing 5% 

Respiratory, thoracic and  
mediastinal disorders 

Cough 12% 
Dyspnoea 11% 
Epistaxis 11% 
Nasal congestion 6% 

Gastrointestinal  
disorders 

Diarrhoea 18% 
Dyspepsia 6% 
Constipation 5% 

Skin and subcutaneous  
tissue disorders 

Acne 7% 
Musculoskeletal and connective  
tissue disorders 

Muscle spasms 18% 
Arthralgia 15% 
Back pain 10% 
Muscle weakness 5% 
Musculoskeletal pain 5% 
Pain in extremities 5% 

General disorders and  
administration site conditions 

Peripheral oedema 16% 
Investigations 

Decreased haemoglobin 6% 
 
Adult maintenance treatment (GPA/MPA Study 2) 
In GPA/MPA Study 2, a total of 57 adult patients with severe, active GPA and MPA were treated with 
MabThera for the maintenance of remission (see section 5.1). 
 



27 

Table 6 Adverse reactions occurring in ≥ 5% of adult patients receiving MabThera in 
GPA/MPA Study 2, and at a higher frequency than the comparator group 

MedDRA System Organ Class 
Adverse  reaction 

Rituximab  
(n=57) 

Infections and infestations   
Bronchitis 14% 
Rhinitis 5% 

Respiratory, thoracic and mediastinal 
disorders 

Dyspnoea 9% 
Gastrointestinal disorders  

Diarrhoea 7% 
General disorders and administration 
site conditions 

 

Pyrexia 9% 
Influenza-like illness 5% 
Oedema peripheral 5% 

Injury, poisoning and procedural 
complications 

 

Infusion-related reactions1 12% 
1Details on infusion related reactions are provided in the description of selected adverse reactions 
section. 

 
The overall safety profile was consistent with the well-established safety profile for MabThera in 
approved autoimmune indications, including GPA/MPA. Overall, 4% of patients in the MabThera arm 
experienced adverse events leading to discontinuation. Most adverse events in the MabThera arm were 
mild or moderate in intensity.  No patients in the MabThera arm had fatal adverse events. 
 
The most commonly reported events considered as ADRs were infusion-related reactions and 
infections.   
 
Long-term follow-up (GPA/MPA Study 3) 
In a long-term observational safety study, 97 GPA/MPA patients received treatment with MabThera 
(mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician’s standard practice 
and discretion.  The overall safety profile was consistent with the well-established safety profile of 
MabThera in RA and GPA/MPA and no new adverse reactions were reported.    
 
Paediatric population  
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, MabThera was given at the 
discretion of the investigator (17 out of 25 patients received additional MabThera 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 study 
period), IRRs (15 patients [60%] in the remission induction phase; 17 patients [68%] in the overall 
study period), and nausea (4 patients [16%] in the remission induction phase; 5 patients [20%] in the 
overall study period).    
 
During the overall study period, the safety profile of MabThera was consistent with that reported 
during the remission induction phase. 
 



28 

The safety profile of MabThera in paediatric GPA or MPA patients was consistent in type, nature and 
severity with the known safety profile in adult patients in the approved autoimmune indications, 
including adult GPA or MPA.    
 
Description of selected adverse  reactions 
 
Infusion-related reactions 
In GPA/MPA Study 1 (adult induction of remission study), IRRs were defined as any adverse event 
occurring within 24 hours of an infusion and considered to be infusion-related by investigators in the 
safety population. Of the 99 patients treated with MabThera, 12 (12%) experienced at least one IRR. 
All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, 
flushing, throat irritation, and tremor. MabThera was given in combination with intravenous 
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 MabThera arm 
experienced at least one infusion-related reaction.  The incidence of IRR symptoms was highest during 
or after the first infusion (9%) and decreased with subsequent infusions (<4%). All IRR symptoms 
were mild or moderate and most of them were reported from the SOCs Respiratory, Thoracic and 
Mediastinal Disorders and Skin and Subcutaneous Tissue disorders.  
 
In the clinical trial in paediatric patients with GPA or MPA, the reported IRRs were predominantly seen 
with the first infusion (8 patients [32%]), and then decreased over time with the number of MabThera 
infusions (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 those 
known in adult GPA or MPA patients treated with MabThera.  The majority of IRRs were Grade 1 and 
Grade 2, there were two non-serious Grade 3 IRRs, and no Grade 4 or 5 IRRs reported.  One serious 
Grade 2 IRR (generalized oedema which resolved with treatment) was reported in one patient (see 
section 4.4). 
 
Infections  
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 moderate and 
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 frequently reported 
serious infection in the MabThera group was pneumonia at a frequency of 4%. 
 
In GPA/MPA Study 2, 30/57 (53%) patients in the MabThera arm experienced infections. The 
incidence of all grade infections was similar between the arms. Infections were predominately mild to 
moderate. The most common infections in the MabThera arm included upper respiratory tract 
infections, gastroenteritis, urinary tract infections and herpes zoster. The incidence of serious 
infections was similar in both arms (approximately 12%). The most commonly reported serious 
infection in the MabThera group was mild or moderate bronchitis. 
 
In the clinical trial in paediatric patients with severe, active GPA and MPA, 91% of reported infections 
were non-serious and 90% were mild to moderate.  
 
The most common infections in the overall phase were: upper respiratory tract infections (URTIs) 
(48%), influenza (24%), conjunctivitis (20%), nasopharyngitis (20%), lower respiratory tract 
infections (16%), sinusitis (16%), viral URTIs (16%), ear infection (12%), gastroenteritis (12%), 
pharyngitis (12%), urinary tract infection (12%).  Serious infections were reported in 7 patients (28%), 
and included: influenza (2 patients [8%]) and lower respiratory tract infection (2 patients [8%]) as the 
most frequently reported events. 
 



29 

Malignancies 
In GPA/MPA Study 1, the incidence of malignancy in MabThera treated patients in the GPA and 
MPA clinical study was 2.00 per 100 patient years at the study common closing date (when the final 
patient had completed the follow-up period).  On the basis of standardised incidence ratios, the 
incidence of malignancies appears to be similar to that previously reported in patients with 
ANCA-associated vasculitis. 
 
In the paediatric clinical trial, no malignancies were reported with a follow-up period of up to 54 
months. 
 
Cardiovascular adverse reactions 
In GPA/MPA Study 1, cardiac events occurred at a rate of approximately 273 per 100 patient years 
(95% CI 149-470) at the 6-month primary endpoint.  The rate of serious cardiac events was 2.1 per 
100 patient years (95% CI 3 -15).  The most frequently reported events were tachycardia (4%) and 
atrial fibrillation (3%) (see section 4.4). 
 
Neurologic events 
Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior 
leukoencephalopathy syndrome (RPLS) have been reported in autoimmune conditions. Signs and 
symptoms included visual disturbance, headache, seizures and altered mental status, with or without 
associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The 
reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, 
hypertension, immunosuppressive therapy and/or chemotherapy. 
 
Hepatitis-B reactivation 
A small number of cases of hepatitis-B reactivation, some with fatal outcome, have been reported in 
granulomatosis with polyangiitis and microscopic polyangiitis patients receiving MabThera in the 
postmarketing setting. 
 
Hypogammaglobulinaemia 
Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in 
adult and pediatric GPA and MPA patients treated with MabThera.  
 
In GPA/MPA Study 1, at 6 months, in the MabThera group, 27%, 58% and 51% of patients with 
normal immunoglobulin levels at baseline had low IgA, IgG and IgM levels, respectively, compared to 
25%, 50% and 46% in the cyclophosphamide group. The rate of overall infections and serious 
infections 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 or 
decreases 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 of 
hypogammaglobulinaemia, 18 patients (72%) had prolonged (defined as Ig levels below lower limit of 
normal 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 increased 
risk of serious infection in these patients. The consequences of long term B cell depletion in paediatric 
patients are unknown. 

Neutropenia 
In GPA/MPA Study 1, 24% of patients in the MabThera group (single course) and 23% of patients in 
the cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not 
associated with an observed increase in serious infection in MabThera-treated patients.   
 
In GPA/MPA Study 2, the incidence of all-grade neutropenia was 0% for MabThera-treated patients 
vs 5% for azathioprine treated patients. 
 



30 

Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Experience from pemphigus vulgaris 
 
Summary of the safety profile in PV Study 1 (Study ML22196) and PV Study 2 (Study WA29330) 
The safety profile of MabThera in combination with short-term, low-dose glucocorticoids in the 
treatment 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 MabThera group (PV Study 1). Patients randomised to the MabThera group 
received an initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15. 
Maintenance doses of 500 mg IV were administered at months 12 and 18. Patients could receive 
1000 mg IV at the time of relapse (see section 5.1).   
 
In PV Study 2, a randomized, double-blind, double-dummy, active-comparator, multicenter study 
evaluating the efficacy and safety of MabThera compared with mycophenolate mofetil (MMF) in 
patients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment 
with MabThera (initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15 
repeated at Weeks 24 and 26) for up to 52 weeks (see section 5.1).  
 
The safety profile of MabThera in PV was consistent with the established safety profile in other 
approved autoimmune indications.   
 
Tabulated list of adverse reactions for PV Studies 1 and 2 
Adverse reactions from PV Studies 1 and 2 are presented in Table 7. In PV Study 1, ADRs were 
defined as adverse events which occurred at a rate of  ≥ 5% among MabThera-treated PV patients, 
with a  ≥ 2% absolute difference in incidence between the MabThera-treated group and the standard-
dose prednisone group up to month 24.  No patients were withdrawn due to ADRs  in Study 1. In PV 
Study 2, ADRs were defined as adverse events occurring in ≥5% of patients in the MabThera arm and 
assessed as related. 
 



31 

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

MedDRA System Organ Class Very Common Common 
Infections and infestations Upper respiratory tract infection Herpes virus infection 

Herpes zoster 
Oral herpes 
Conjunctivitis 
Nasopharyngitis 
Oral candidiasis 
Urinary tract infection 

Neoplasms Benign, Malignant and 
Unspecified (incl cysts and polyps) 

 Skin papilloma 

Psychiatric disorders Persistent depressive disorder Major depression 
Irritability 

Nervous system disorders Headache 
 

Dizziness 

Cardiac disorders  Tachycardia 
Gastrointestinal disorders  Abdominal pain upper 
Skin and subcutaneous tissue disorders Alopecia Pruritus 

Urticaria 
Skin disorder 

Musculoskeletal, connective tissue and 
bone disorders 

 Musculoskeletal pain 
Arthralgia 
Back pain 

General disorders and administration site 
conditions 

 Fatigue 
Asthenia 
Pyrexia 

Injury, Poisoning and Procedural 
Complications 

Infusion-related reactions*  

*Infusion-related reactions for PV Study 1 included symptoms collected on the next scheduled visit after each infusion, 
and adverse events occurring on the day of or one day after the infusion.  The most common infusion-related reaction 
symptoms/Preferred Terms for PV Study 1 included headaches, chills, high blood pressure, nausea, asthenia and pain. 
 
The most common infusion-related reaction symptoms/Preferred Terms for PV Study 2 were dyspnoea, erythema, 
hyperhidrosis, flushing/hot flush, hypotension/low blood pressure and rash/rash pruritic. 

 
Description of selected adverse reactions 
 
Infusion-related reactions 
In PV Study 1, infusion-related reactions were common (58%). Nearly all infusion-related reactions 
were 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 those 
seen in RA and GPA/MPA patients. 
 
In PV Study 2, IRRs occurred primarily at the first infusion and the frequency of IRRs decreased with 
subsequent 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 MabThera 
treatment; three of the four patients experienced serious (life-threatening) IRRs.  Serious IRRs 
occurred at the first (2 patients) or second (1 patient) infusion and resolved with symptomatic 
treatment.   
 



32 

Infections 
In PV Study 1, 14 patients (37%) in the MabThera group experienced treatment-related infections 
compared to 15 patients (42%) in the standard-dose prednisone group. The most common infections in 
the MabThera group were herpes simplex and zoster infections, bronchitis, urinary tract infection, 
fungal infection and conjunctivitis. Three patients (8%) in the MabThera group experienced a total of 
5 serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, 
lung infection, Staphylococcal sepsis) and one patient (3%) in the standard-dose prednisone group 
experienced a serious infection (Pneumocystis jirovecii pneumonia).  
 
In PV Study 2, 42 patients (62.7%) in the MabThera arm experienced infections.  The most common 
infections in the MabThera group were upper respiratory tract infection, nasopharyngitis, oral 
candidiasis and urinary tract infection.  Six patients (9%) in the MabThera arm experienced serious 
infections. 
 
Laboratory abnormalities 
PV Study 2, in the MabThera arm, transient decreases in lymphocyte count, driven by decreases in the 
peripheral T-cell populations, as well as a transient decrease in phosphorus level were very commonly 
observed post-infusion. These were considered to be induced by IV methylprednisolone premedication 
infusion. 
 
In PV Study 2, low IgG levels were commonly observed and low IgM levels were very commonly 
observed; however, there was no evidence of an increased risk of serious infections after the 
development of low IgG or IgM. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Limited experience with doses higher than the approved dose of intravenous MabThera formulation is 
available from clinical trials in humans. The highest intravenous dose of MabThera tested in humans 
to date is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. No additional 
safety signals were identified. 
 
Patients who experience overdose should have immediate interruption of their infusion and be closely 
monitored. 
 
In the postmarketing setting five cases of MabThera overdose have been reported. Three cases had no 
reported adverse event. The two adverse events that were reported were flu-like symptoms, with a 
dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02 
 
Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated 
phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95 % of all 
B cell non-Hodgkin’s lymphomas.  
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


33 

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, 
pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon 
antibody binding and is not shed from the cell surface. CD20 does not circulate in the plasma 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 can 
recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated 
cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and 
antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the 
surface of granulocytes, macrophages and NK cells. Rituximab binding to CD 20 antigen on B 
lymphocytes has also been demonstrated to induce cell death via apoptosis. 
 
Peripheral B cell counts declined below normal following completion of the first dose of MabThera. In 
patients treated for haematological malignancies, B cell recovery began within 6 months of treatment 
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 months post-induction 
therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was 
observed following two infusions of 1000 mg MabThera separated by a 14-day interval. Peripheral 
blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the 
majority of patients by week 40, whether MabThera was administered as monotherapy or in 
combination with methotrexate. A small proportion of patients had prolonged peripheral B cell 
depletion lasting 2 years or more after their last dose of MabThera. In patients with GPA or MPA, the 
number of peripheral blood B cells decreased to <10 cells/μL after two weekly infusions of rituximab 
375 mg/m2, and remained 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 by month 12, increasing to 
87% of patients by month 18. 
 
Clinical experience in Non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia 
 
Follicular lymphoma 
 
Monotherapy 
 
Initial treatment, weekly for 4 doses  
In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL 
received 375 mg/m2 of MabThera as an intravenous infusion once weekly for four weeks. The overall 
response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI95% 41% - 56%) with a 6% 
complete response (CR) and a 42 % partial response (PR) rate. The projected median time to 
progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was 
higher in 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 as 
duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with 
autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT. Neither 
age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high 
LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) on 
response to MabThera. A statistically significant correlation was noted between response rates and 
bone marrow involvement. 40% of patients with bone marrow involvement responded compared to 
59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a 
stepwise logistic regression analysis in which the following factors were identified as prognostic 
factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky 
disease. 
 



34 

Initial treatment, weekly for 8 doses  
In a multi-centre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular 
B cell NHL received 375 mg/m2 of MabThera as intravenous infusion weekly for eight doses. The 
ORR was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a projected 
median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months). 
 
Initial treatment, bulky disease, weekly for 4 doses  
In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (single 
lesion ≥ 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m2 of MabThera as 
intravenous infusion weekly for four doses. The ORR was 36 % (CI95% 21% – 51%; CR 3%, PR 33%) 
with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months). 
 
Re-treatment, weekly for 4 doses  
In a multi-centre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular 
B cell NHL, who had achieved an objective clinical response to a prior course of MabThera, were 
re-treated with 375 mg/m2 of MabThera as intravenous infusion weekly for four doses. Three of the 
patients had received two courses of MabThera before enrolment and thus were given a third course in 
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 responding patients 
of 17.8 months (range 5.4 – 26.6). This compares favourably with the TTP achieved after the prior 
course of MabThera (12.4 months). 
 
Initial treatment, in combination with chemotherapy 
 
In an open-label randomised trial, a total of 322 previously untreated patients with follicular 
lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2, 
vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 
1 -5) every 3 weeks for 8 cycles or MabThera 375 mg/m2 in combination with CVP (R-CVP). 
MabThera 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 of patients 
was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to 
treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with 
a tumour response (CR, CRu, PR) was significantly higher (p< 0.0001 Chi-Square test) in the R-CVP 
group (80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time 
to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively 
(p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and 
was 13.5 months in the CVP group (p < 0.0001, log-rank test).  
 
The difference between the treatment groups with respect to overall survival showed a significant 
clinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were 80.9% 
for patients in the R-CVP group compared to 71.1% for patients in the CVP group. 
 
Results from three other randomised trials using MabThera in combination with chemotherapy 
regimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant 
improvements in response rates, time-dependent parameters as well as in overall survival. Key results 
from all four studies are summarised in Table 8.  
 



35 

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

Study 
Treatment, 

N 

Median 
FU,  
months 

ORR, % CR, % 

Median 
TTF/PFS/ EFS,  
months 

OS 
rates, 
% 

M39021 
CVP, 159 
R-CVP, 162 53 

57 
81 

10 
41 

Median TTP: 
14.7 
33.6 

P<0.0001 

53-months  
71.1 
80.9 

p=0.029 

GLSG’00 
CHOP, 205 
R-CHOP, 223 

18 
90 
96 

17 
20 

Median TTF: 2.6 
years 

Not reached 
p < 0.001 

18-months 
90 
95 

p = 0.016 

OSHO-39 
MCP, 96 
R-MCP, 105 

47 
75 
92 

25  
50 

Median PFS: 28.8 
Not reached 
p < 0.0001 

48-months 
74  
87  

p = 0.0096 

FL2000 

CHVP-IFN, 
183 
R-CHVP-IFN, 
175 

42 
85  
94 

49 
76 

Median EFS: 36  
Not reached 
p < 0.0001 

42-months 
84  
91 

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 
 
Maintenance therapy 
 
Previously untreated follicular lymphoma  
In a prospective, open label, international, multi-centre, phase III trial 1193 patients with previously 
untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP 
(n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1078 patients responded 
to induction therapy, of which 1018 were randomised to MabThera maintenance therapy (n=505) or 
observation (n=513). The two treatment groups were well balanced with regards to baseline 
characteristics and disease status. MabThera maintenance treatment consisted of a single infusion of 
MabThera at 375 mg/m2 body surface area given every 2 months until disease progression or for a 
maximum period of two years.  
 
The pre-specified primary analysis was conducted at a median observation time of 25 months from 
randomization, maintenance therapy with MabThera resulted in a clinically relevant and statistically 
significant improvement in the primary endpoint of investigator assessed progression-free survival 
(PFS) as compared to observation in patients with previously untreated follicular lymphoma (Table 9).  
 
Significant benefit from maintenance treatment with MabThera was also seen for the secondary 
endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next 
chemotherapy (TNCT) and overall response rate (ORR) in the primary analysis (Table 9).  
 
Data from extended follow-up of patients in the study (median follow-up 9 years) confirmed the long-
term benefit of MabThera maintenance therapy in terms of PFS, EFS, TNLT and TNCT (Table 9). 
 



36 

Table 9 Overview of efficacy results for MabThera maintenance vs. observation at the 
protocol-defined primary analysis and after 9 years median follow-up (final 
analysis) 

 Primary analysis 
(median FU: 25 months) 

Final analysis 
(median FU: 9.0 years) 

Observation 
N=513 

MabThera 
N=505 

Observation 
N=513 

MabThera 
N=505 

Primary efficacy     
Progression-free survival (median) NR NR 4.06 years 10.49 years 
log-rank p value <0.0001 <0.0001 
hazard ratio (95% CI) 
risk reduction 

0.50 (0.39, 0.64) 
50% 

0.61 (0.52, 0.73) 
39% 

Secondary efficacy     
Overall survival (median) NR NR NR NR 
log-rank p value 0.7246 0.7948 
hazard ratio (95% CI) 
risk reduction 

0.89 (0.45, 1.74) 
11% 

1.04 (0.77, 1.40) 
-6% 

Event-free survival (median) 38 months NR 4.04 years 9.25 years 
log-rank p value <0.0001 <0.0001 
hazard ratio (95% CI) 
risk reduction  

0.54 (0.43, 0.69) 
46% 

0.64 (0.54, 0.76) 
36% 

TNLT (median) NR NR 6.11 years NR 
log-rank p value 0.0003 <0.0001 
hazard ratio (95% CI) 
risk reduction  

0.61 (0.46, 0.80) 
39% 

0.66 (0.55, 0.78) 
34% 

TNCT (median) NR NR 9.32 years NR 
log-rank p value 0.0011 0.0004 
hazard ratio (95% CI) 
risk reduction  

0.60 (0.44, 0.82) 
40% 

0.71 (0.59, 0.86) 
39% 

Overall response rate* 55% 74% 61% 79% 
chi-squared test p value <0.0001 <0.0001 
odds 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 <0.0001 
odds ratio (95% CI) 2.21 (1.65, 2.94) 2.34 (1.80, 3.03)  

* at end of maintenance/observation; final analysis results based on median follow-up of 73 months.  
FU: follow-up; NR: not reached at time of clinical cut off, TNCT: time to next chemotherapy treatment; TNLT: time to next 
anti lymphoma treatment. 
 
MabThera maintenance treatment provided consistent benefit in all predefined subgroups tested: 
gender (male, female), age (< 60 years, >= 60 years), FLIPI score (<=1, 2 or >= 3), induction therapy 
(R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment (CR, 
CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less pronounced 
effect in elderly patients (> 70 years of age), however sample sizes were small. 
 
Relapsed/Refractory follicular lymphoma  
 
In a prospective, open label, international, multi-centre, phase III trial, 465 patients with 
relapsed/refractory follicular lymphoma were randomised in a first step to induction therapy with 
either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or MabThera plus 
CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard to baseline 
characteristics and disease status. A total of 334 patients achieving a complete or partial remission 
following induction therapy were randomised in a second step to MabThera maintenance therapy 
(n=167) or observation (n=167). MabThera maintenance treatment consisted of a single infusion of 
MabThera at 375 mg/m2 body surface area given every 3 months until disease progression or for a 
maximum period of two years.  
 



37 

The final efficacy analysis included all patients randomised to both parts of the study. After a median 
observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly 
improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to 
CHOP (see Table 10). 
 
Table 10 Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months 

median observation time)  
 CHOP R-CHOP p-value Risk Reduction1) 

Primary efficacy      
ORR2) 74 % 87 % 0.0003 Na 

CR2) 16 % 29 % 0.0005 Na 
PR2) 58 % 58 % 0.9449 Na 

1) Estimates were calculated by hazard ratios 
2) Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend 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 28 
months from maintenance randomisation. Maintenance treatment with MabThera led to a clinically 
relevant and statistically significant improvement in the primary endpoint, PFS, (time from 
maintenance randomisation to relapse, disease progression or death) when compared to observation 
alone (p< 0.0001 log-rank test).  The median PFS was 42.2 months in the MabThera maintenance arm 
compared to 14.3 months in the observation arm. Using a cox regression analysis, the risk of 
experiencing progressive disease or death was reduced by 61% with MabThera maintenance treatment 
when compared to observation (95% CI; 45%-72%). Kaplan-Meier estimated progression-free rates at 
12 months were 78% in the MabThera maintenance group vs. 57 % in the observation group. An 
analysis of overall survival confirmed the significant benefit of MabThera maintenance over 
observation (p=0.0039 log-rank test). MabThera maintenance treatment reduced the risk of death by 
56% (95% CI; 22%-75%).  
 
Table 11 Maintenance phase: overview of efficacy results MabThera vs. observation (28 

months median observation time)  
Efficacy Parameter Kaplan-Meier Estimate of  

Median Time to Event (Months) 
Risk 

Reduction 
Observation 

(N = 167) 
MabThera 

(N=167) 
Log-Rank  

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

Overall survival  NR NR 0.0039 56 % 

Time to new lymphoma 
treatment 

20.1 38.8 < 0.0001 50 % 

Disease-free survivala 16.5 53.7 0.0003 67 % 
Subgroup analysis     
PFS 

CHOP 
R-CHOP 

CR 
PR 

 
OS 

CHOP 
R-CHOP 

 

 
11.6 
22.1 
14.3 
14.3 

 
 

NR 
NR 

 
37.5 
51.9 
52.8 
37.8 

 
 

NR 
NR 

 
< 0.0001 
0.0071 
 0.0008 

< 0.0001 
 
 

0.0348 
0.0482 

 
71 % 
46 % 
64 % 
54 % 

 
 

55 % 
56 % 

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



38 

The benefit of MabThera maintenance treatment was confirmed in all subgroups analysed, regardless 
of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) 
(Table 11). MabThera maintenance treatment significantly prolonged median PFS in patients 
responding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p< 0.0001) as well 
as in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). 
Although subgroups were small, MabThera maintenance treatment provided a significant benefit 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 80 
years) with diffuse large B cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 
750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and 
prednisolone 40 mg/m2/day on days 1-5) every 3 weeks for eight cycles, or MabThera 375 mg/m2 plus 
CHOP (R-CHOP). MabThera was administered on the first day of the treatment cycle.  
 
The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a 
median follow-up duration of approximately 31 months. The two treatment groups were well balanced 
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 in the 
duration of event-free survival (the primary efficacy parameter; where events were death, relapse or 
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 arm compared 
to 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months, estimates for 
overall survival were 68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequent 
analysis of the duration of overall survival, carried out with a median follow-up duration of 60 months, 
confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), representing a risk reduction of 
32%. 
 
The analysis of all secondary parameters (response rates, progression-free survival, disease-free 
survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The 
complete 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 all patient 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 for event-free survival and overall survival (R-CHOP compared with CHOP) were less than 
0.83 and 0.95 respectively. R-CHOP was associated with improvements in outcome for both high- and 
low-risk patients according to age adjusted IPI. 
 
Clinical laboratory findings  
 
Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of 
356 patients evaluated for anti-drug antibody (ADA), 1.1 % (4 patients) were positive. 
 
Chronic lymphocytic leukaemia 
 
In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients with 
relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, 
cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or MabThera in combination with 
FC (R-FC). MabThera was administered at a dosage of 375 mg/m2 during the first cycle one day prior 
to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients 
were excluded from the study in relapsed/refractory CLL if they had previously been treated with 
monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for 
at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 
FC) for the first-line study (Table 12a and Table 12b) and 552 patients (276 R-FC, 276 FC) for the 
relapsed/refractory study (Table 13) were analysed for efficacy. 



39 

 
In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months 
in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overall 
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 most patient 
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 MabThera plus FC vs. FC alone - 48.1 months 
median observation time 

Efficacy Parameter Kaplan-Meier Estimate of  
Median Time to Event (Months) 

Risk 
Reduction 

FC 
(N = 409) 

R-FC 
(N=408) 

Log-Rank  
p value 

Progression-free survival (PFS) 32.8 55.3 <0.0001 45% 
Overall survival  NR NR 0.0319 27% 
Event free survival 31.3 51.8 <0.0001 44% 
Response rate (CR, nPR, or PR) 72.6% 85.8% <0.0001 n.a. 

CR rates 16.9% 36.0% <0.0001  n.a. 
Duration of response* 36.2 57.3 <0.0001 44% 
Disease free survival (DFS)** 48.9 60.3 0.0520 31% 
Time to new treatment 47.2 69.7 <0.0001 42% 

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; n.a.: not applicable 
*: only applicable to patients achieving a CR, nPR, PR 
**: only applicable to patients achieving a CR 
 
Table 12b First-line treatment of chronic lymphocytic leukaemia 

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

Progression-free survival (PFS) 
 

Number of 
patients 

Hazard Ratio 
(95% CI) 

p-value (Wald 
test, not 

adjusted) FC R-FC 
Binet stage A 22 18 0.39 (0.15; 0.98) 0.0442 
Binet stage B 259 263 0.52 (0.41; 0.66) <0.0001 
Binet stage C 126 126 0.68 (0.49; 0.95) 0.0224 

CI: Confidence Interval 
 
In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6 
months in the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). The benefit in 
terms of PFS was observed in almost all patient subgroups analysed according to disease risk at 
baseline. A slight but not significant improvement in overall survival was reported in the R-FC 
compared to the FC arm.  
 



40 

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

Efficacy Parameter Kaplan-Meier Estimate of  
Median Time to Event (Months) 

Risk 
Reduction 

FC 
(N = 276) 

R-FC 
(N=276) 

Log-Rank  
p value 

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

Overall survival  51.9 NR 0.2874 17% 
     

Event free survival 19.3 28.7 0.0002 36% 

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

CR rates 13.0% 24.3% 0.0007  n.a. 

 Duration of response * 27.6 39.6 0.0252 31% 
Disease free survival (DFS)** 42.2 39.6 0.8842 -6% 
Time to new CLL treatment 34.2 NR 0.0024 35% 

Response rate and CR rates analysed using Chi-squared Test. 
*: only applicable to patients achieving a CR, nPR, PR;          NR: not reached                  n.a. not applicable  
**: only applicable to patients achieving a CR;      
 
Results from other supportive studies using MabThera in combination with other chemotherapy 
regimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment of 
previously untreated and/or relapsed/refractory CLL patients have also demonstrated high overall 
response rates with benefit in terms of PFS rates, albeit with modestly higher toxicity (especially 
myelotoxicity). These studies support the use of MabThera with any chemotherapy. 
Data in approximately 180 patients pre-treated with MabThera have demonstrated clinical benefit 
(including CR) and are supportive for MabThera re-treatment. 
 
Paediatric population 
 
A multicenter, open-label, randomized study of Lymphome Malin B (LMB) chemotherapy 
(corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, 
etoposide and triple drug  [methotrexate/cytarabine/ corticosteroid] intrathecal therapy) alone or in 
combination with MabThera was conducted in paediatric patients with previously untreated advanced 
stage CD20 positive DLBCL/BL/BAL/BLL. Advanced stage is defined as Stage III with elevated 
LDH level (“B-high”), [LDH > twice the institutional upper limit of the adult normal values (> Nx2)] 
or any stage IV or BAL. Patients were randomized to receive either LMB chemotherapy or six IV 
infusions of MabThera at a dose of 375mg/m2 BSA in combination with LMB chemotherapy (two 
during each of the two induction courses and one during each of the two consolidation courses) as per 
the LMB scheme. A total of 328 randomized patients were included in the efficacy analyses, of which 
one patient under 3 years of age received MabThera in combination with LMB chemotherapy. 
 
The two treatment arms, LMB (LMB chemotherapy) and R-LMB (LMB chemotherapy with 
MabThera), were well balanced with regards to baseline characteristics.  Patients had a median age of 
7 and 8 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 Murphy 
staging, most patients were either BL stage III (45.7% in the LMB arm and 43.3% in the R-LMB arm) 
or BAL, CNS negative (21.3% in the LMB arm and 24.4% in the R-LMB arm). Less than half of the 
patients (45.1% in both arms) had bone marrow involvement, and most patients (72.6% in the LMB 
arm and 73.2% in the R-LMB arm) had no CNS involvement. The primary efficacy endpoint was 



41 

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 the 
second CYVE course, whichever occurs first. The secondary efficacy endpoints were OS and CR 
(complete remission).  
 
At the pre-specified interim analysis with approximately 1 year of median follow-up, clinically 
relevant improvement in the primary endpoint of EFS was observed, with 1-year rate estimates of 
94.2% (95% CI, 88.5% - 97.2%) in the R-LMB arm vs. 81.5% (95% CI, 73.0% - 87.8%) in the LMB 
arm, and adjusted Cox HR 0.33 (95% CI, 0.14 – 0.79). Upon IDMC (independent data monitoring 
committee) recommendation based on this result, the randomization was halted and patients in the 
LMB arm were allowed to cross over to receive MabThera.   
 
Primary efficacy analyses were performed in 328 randomized patients with a median follow-up of 3.1 
years. The results are described in Table 14. 
 
Table 14: Overview of Primary Efficacy Results (ITT population) 

Analysis LMB 
(N = 164) 

R-LMB 
(N=164) 

EFS 28 events 10 events 

One-sided log-rank test p-value 0.0006 

Adjusted Cox HR 0.32 (90% CI: 0.17, 0.58) 

3-year EFS rates 82.3% 
(95% CI: 75.7%, 87.5%) 

93.9% 
(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% CI: 81.2%, 91.6%) 

95.1% 
(95% CI: 90.5%, 97.5%) 

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

 
The primary efficacy analysis showed an EFS benefit of MabThera addition to LMB chemotherapy 
over LMB chemotherapy alone, with an EFS HR 0.32 (90% CI 0.17 - 0.58) from a Cox regression 
analysis adjusting for national group, histology, and therapeutic group. While no major differences in 
numbers of patients achieving CR was observed between the two treatment groups, the benefit of 
MabThera addition to LMB chemotherapy was also shown in the secondary endpoint of OS, with the 
OS HR of 0.36 (95% CI, 0.16 – 0.81). 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
MabThera in all subsets of the paediatric population with follicular lymphoma and CLL, and in the 
paediatric population from birth to < 6 months of age in CD20 positive diffuse large B-cell lymphoma.  
See Section 4.2 for information on paediatric use. 
 
Clinical experience in rheumatoid arthritis 
 
The efficacy and safety of MabThera in alleviating the symptoms and signs of rheumatoid arthritis in 
patients with an inadequate response to TNF-inhibitors was demonstrated in a pivotal randomised, 
controlled, double-blind, multicenter trial (Trial 1).  
 



42 

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one or 
more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to 
the criteria of the American College of Rheumatology (ACR). MabThera was administered as two IV 
infusions separated by an interval of 15 days. Patients received 2 x 1000 mg intravenous infusions of 
MabThera or placebo in combination with MTX. All patients received concomitant 60 mg oral 
prednisone on days 2-7 and 30 mg on days 8-14 following the first infusion. The primary endpoint was 
the proportion of patients who achieved an ACR20 response at week 24. Patients were followed 
beyond week 24 for long term endpoints, including radiographic assessment at 56 weeks and at 104 
weeks. During this time, 81% of patients, from the original placebo group received MabThera between 
weeks 24 and 56, under an open label extension study protocol.  
 
Trials of MabThera in patients with early arthritis (patients without prior methotrexate treatment and 
patients with an inadequate response to methotrexate, but not yet treated with TNF-alpha inhibitors) 
have met their primary endpoints.  MabThera is not indicated for these patients, since the safety data 
about long-term MabThera treatment are insufficient, in particular concerning the risk of development 
of malignancies and PML. 
 
Disease activity outcomes 
MabThera in combination with methotrexate significantly increased the proportion of patients 
achieving at least a 20 % improvement in ACR score compared with patients treated with 
methotrexate alone (Table 15). Across all development studies the treatment benefit was similar in 
patients independent of age, gender, body surface area, race, number of prior treatments or disease 
status.  
 
Clinically and statistically significant improvement was also noted on all individual components of the 
ACR response (tender and swollen joint counts, patient and physician global assessment, disability 
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 MabThera+MTX 
(2 x 1000 mg) 

Trial 1  
 

 N= 201 N= 298 
 

 ACR20 36 (18%) 153 (51%)*** 
 ACR50 11 (5%) 80 (27%)*** 
 ACR70 3 (1%) 37 (12%)*** 
 EULAR Response 

(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 timepoint: ***p ≤ 0.0001 
 
Patients treated with MabThera in combination with methotrexate had a significantly greater reduction 
in disease activity score (DAS28) than patients treated with methotrexate alone (Table 15). Similarly, 
a good to moderate European League Against Rheumatism (EULAR) response was achieved by 
significantly more MabThera treated patients treated with MabThera and methotrexate compared to 
patients treated with methotrexate alone (Table 15). 
 
Radiographic response 
Structural joint damage was assessed radiographically and expressed as change in modified Total 
Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score. 
 
In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitor 
therapies, receiving MabThera in combination with methotrexate demonstrated significantly less 
radiographic progression than patients originally receiving methotrexate alone at 56 weeks. Of the 
patients originally receiving methotrexate alone, 81 % received MabThera either as rescue between 



43 

weeks 16-24 or in the extension trial, before week 56. A higher proportion of patients receiving the 
original MabThera/MTX treatment also had no erosive progression over 56 weeks (Table 16). 
 
Table 16 Radiographic outcomes at 1 year (mITT population) 

 Placebo+MTX 
 

MabThera+MTX 
2 × 1000 mg 

 
Trial 1 (n = 184) (n = 273) 
Mean change from baseline:   

Modified total sharp score 2.30 1.01* 
 

Erosion score 1.32 0.60* 
 

Joint space narrowing score 0.98 0.41** 
 

Proportion of patients with no radiographic 
change 

46% 53%, NS 

Proportion of patients with no erosive change  52% 60%, NS 
 

150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX by one year 
* p <0.05, ** p < 0.001. Abbreviation: NS, non significant  
 
Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis 
at 2 years in Trial 1 demonstrated significantly reduced progression of structural joint damage in 
patients receiving MabThera in combination with methotrexate compared to methotrexate alone as 
well as a significantly higher proportion of patients with no progression of joint damage over the 2-
year period. 
 
Physical function and quality of life outcomes 
Significant reductions in disability index (HAQ-DI) and fatigue (FACIT-Fatigue) scores were 
observed in patients treated with MabThera compared to patients treated with methotrexate alone. The 
proportions of MabThera treated patients showing a minimal clinically important difference (MCID) 
in HAQ-DI (defined as an individual total score decrease of >0.22) was also higher than among 
patients receiving methotrexate alone (Table 17). 
 
Significant improvement in health-related quality of life was also demonstrated with significant 
improvement in both the physical health score (PHS) and mental health score (MHS) of the SF-36. 
Further, a significantly higher proportion of patients achieved MCIDs for these scores (Table 17). 
 
Table 17 Physical function and quality of life outcomes at week 24 in Trial 1 

Outcome† Placebo+MTX MabThera+MTX 
(2 x 1000 mg) 

 
 
Mean change in HAQ-DI 

n=201 
 

0.1 

n=298 
 

-0.4*** 
% HAQ-DI MCID 20% 51% 
Mean change in FACIT-T -0.5 -9.1*** 
 
 
Mean Change in SF-36 PHS 

n=197 
 

0.9 

n=294 
 

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 
 



44 

Efficacy in autoantibody (RF and or anti-CCP) seropositive patients  
Patients seropositive to Rheumatoid Factor (RF) and/or anti- Cyclic Citrullinated Peptide (anti-CCP) 
who were treated with MabThera in combination with methotrexate showed an enhanced response 
compared to patients negative to both. 
 
Efficacy outcomes in MabThera treated patients were analysed based on autoantibody status prior to 
commencing treatment. At Week 24, patients who were seropositive to RF and/or anti-CCP at baseline 
had a significantly increased probability of achieving ACR20 and 50 responses compared to 
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 of achieving ACR70. At 
week 48 seropositive patients were 2-3 times more likely to achieve ACR responses compared to 
seronegative patients. Seropositive patients also had a significantly greater decrease in DAS28-ESR 
compared to seronegative patients (Figure 1). 
 
Table 18 Summary of efficacy by baseline autoantibody status 

 Week 24 Week 48 
 Seropositive 

(n=514) 
Seronegative 

(n=106) 
Seropositive 

(n=506) 
Seronegative 

(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 

 
 
Long-term efficacy with multiple course therapy 
Treatment with MabThera in combination with methotrexate over multiple courses resulted in 
sustained 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 of patients 
achieving MCID for HAQ-DI were observed. 
 



45 

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

 
 
Clinical laboratory findings 
 
A total of 392/3095 (12.7%) patients with rheumatoid arthritis tested positive for ADAin clinical 
studies following therapy with MabThera. The emergence of ADAwas not associated with clinical 
deterioration or with an increased risk of reactions to subsequent infusions in the majority of patients. 
The presence of ADA may be associated with worsening of infusion or allergic reactions after the 
second infusion of subsequent courses.  
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
MabThera in all subsets of the paediatric population with autoimmune arthritis. See Section 4.2 for 
information on paediatric use. 
 
Clinical experience in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 
 
Adult induction of remission 
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, 
multicenter, 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 MabThera (375 mg/m2) once weekly for 4 weeks. All patients in the 
cyclophosphamide arm received azathioprine maintenance therapy in during follow-up. Patients in 
both arms received 1000 mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose 
glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 
80 mg/day).  Prednisone tapering was to be completed by 6 months from the start of trial treatment.   
 
The primary outcome measure was achievement of complete remission at 6 months defined as a 
Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off 
glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%. 
The trial demonstrated non-inferiority of MabThera to cyclophosphamide for complete remission (CR) 
at 6 months (Table 19). 
 
Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing 
disease (Table 20). 
 

0
10
20
30
40
50
60
70
80
90

1st
Course

2nd
Course

3rd
Course

4th
Course

%
 o

f p
at

ie
nt

s

ACR20

ACR50

ACR70



46 

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

 MabThera  
(n = 99) 

Cyclophosphamide  
(n = 98) 

Treatment Difference 
(MabThera- Cyclophosphamide) 

 
 
Rate 

 
63.6% 

 

 
53.1% 

 

 
10.6% 

95.1%b CI 
 (−3.2%, 24.3%) a 

 
 

− CI = confidence interval. 
− * Worst case imputation 
a Non-inferiority was demonstrated since the lower bound ( − 3.2%) was higher than the pre-determined 

non-inferiority margin ( − 20%). 
b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis. 

 
Table 20  Complete remission at 6-months by disease status 

 MabThera Cyclophosphamide Difference (CI 
95%) 

All patients n=99 n=98  
Newly diagnosed n=48 n=48  
Relapsing n=51 n=50  
Complete remission  
All Patients 63.6% 53.1% 10.6% (-3.2, 24.3) 
Newly diagnosed 60.4% 64.6% − 4.2% (− 23.6, 15.3) 
Relapsing 66.7% 42.0% 24.7% (5.8, 43.6) 

  Worst case imputation is applied for patients with missing data 
 
Complete remission at 12 and 18 months 
In the MabThera 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 for maintenance of 
complete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at 
18 months. From month 12 to month 18, 8 relapses were observed in the MabThera group compared 
with four in the cyclophosphamide group. 
 
Laboratory evaluations 
A total of 23/99 (23%) MabThera-treated patients from the induction of remission trial tested positive 
for ADA by 18 months. None of the 99 MabThera-treated patients were ADA positive at screening.  
There was no apparent trend or negative impact of the presence of ADA on safety or efficacy in the 
induction of remission trial. 
 
Adult maintenance treatment  
A total of 117 patients (88 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associated 
vasculitis) in disease remission were randomized to receive azathioprine (59 patients) or MabThera (58 
patients) in a prospective, multi-center, controlled, open-label study.  Included patients were 21 to 75 
years of age and had newly diagnosed or relapsing disease in complete remission after combined 
treatment with glucocorticoids and pulse cyclophosphamide. The majority of patients were ANCA-
positive at diagnosis or during the course of their disease; had histologically confirmed necrotizing 
small-vessel vasculitis with a clinical phenotype of GPA or MPA, or renal limited ANCA-associated 
vasculitis; or both. 
 
Remission-induction therapy included IV prednisone, administered as per the investigator’s discretion, 
preceded in some patients by methylprednisolone pulses, and pulse cyclophosphamide until remission 
was attained after 4 to 6 months. At that time, and within a maximum of 1 month after the last 
cyclophosphamide pulse, patients were randomly assigned to receive either MabThera (two 500 mg IV 
infusions separated by two weeks (on Day 1 and Day 15) followed by 500 mg IV every 6 months for 18 



47 

months) or azathioprine (administered orally at a dose of 2 mg/kg/day for 12 months, then 1.5 mg/kg/day 
for 6 months, and finally 1 mg/kg/day for 4 months (treatment discontinuation 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 and the 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 MabThera 
infusion or 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.  
 
Results 
At month 28, major relapse (defined by the reappearance of clinical and/or laboratory signs of 
vasculitis activity ([BVAS] > 0) that could lead to organ failure or damage or could be life 
threatening) occurred in 3 patients (5%) in the MabThera group and 17 patients (29%) in the 
azathioprine group (p=0.0007). Minor relapses (not life threatening and not involving major organ 
damage) occurred in seven patients in the MabThera group (12%) and eight patients in the 
azathioprine group (14%).  
 
The cumulative incidence rate curves showed that time to first major relapse was longer in patients 
with MabThera starting from month 2 and was maintained up to month 28 (Figure 3). 
 
Figure 3:  Cumulative incidence over time of first major relapse 

      
 
 

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

Survival Time (Months) 

Pe
rc

en
ta

ge
 o

f P
at

ie
nt

s w
ith

 F
irs

t 
M

aj
or

 R
el

ap
se

 



48 

Paediatric population 
 
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 
 
Study WA25615 (PePRS) was a multicenter, open-label, single-arm, uncontrolled study in 25 
paediatric patients (≥ 2 to < 18 years old) with severe, active GPA or MPA.  The median age of 
patients in 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 a 
minimum of 3 doses of IV methylprednisolone (30 mg/kg/day, not exceeding 1 g/day) prior to the first 
MabThera IV infusion. If clinically indicated, additional daily doses (up to three), of IV 
methylprednisolone could be given. The remission induction regimen consisted of four once weekly 
IV infusions of MabThera at a dose of 375 mg/m2 BSA, on study days 1, 8, 15 and 22 in combination 
with oral prednisolone or prednisone at 1 mg/kg/day (max 60 mg/day) tapered to 0.2 mg/kg/day 
minimum (max 10 mg/day) by Month 6.  After the remission induction phase, patients could, at the 
discretion of the investigator, receive subsequent MabThera infusions on or after Month 6 to maintain 
PVAS remission and control disease activity (including progressive disease or flare) or to achieve first 
remission. 
 
All 25 patients completed all four once weekly IV infusions for the 6-month remission induction 
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 MabThera in 
paediatric GPA and MPA patients (≥ 2 to < 18 years old).  The efficacy objectives of the study were 
exploratory and principally assessed using the Pediatric Vasculitis Activity Score (PVAS) (Table 21). 
 
Cumulative Glucocorticoid dose (IV and Oral) by Month 6: 
Twenty-four out of 25 patients (96%) in Study WA25615 achieved oral glucocorticoid taper to 0.2 
mg/kg/day (or less than or equal to 10 mg/day, whichever was lower) at or by Month 6 during the 
protocol-defined oral steroid taper. 
 
A decrease in median overall oral glucocorticoid use was observed from Week 1 (median = 45 mg 
prednisone equivalent dose [IQR: 35 – 60]) to Month 6 (median = 7.5 mg [IQR: 4-10]), which was 
subsequently maintained at Month 12 (median = 5 mg [IQR: 2-10]) and Mmonth 18 (median =5 mg 
[IQR: 1-5]).  
 
Follow-Up Treatment 
During the Overall Study Period, patients received between 4 and 28 infusions of MabThera (up to 4.5 
yrs [53.8 months]). Patients received up to 375 mg/m2 x 4 of MabThera, approximately every 6 
months at the discretion of the investigator. In total, 17 out of 25 patients (68%) received additional 
rituximab treatment at or post Month 6 until the Common Close Out, 14 out of these 17 patients 
received additional rituximab treatment between Month 6 and Month 18. 
 



49 

Table 21: Study WA25615 (PePRS) - PVAS Remission at Month 1, 2, 4, 6, 12 and 18  
Study visit Number of Responders in PVAS Remission* 

(response rate [%]) 

n=25 

95% CIα 

 Month 1 0 0.0%, 13.7% 

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

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

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

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

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

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

 
Laboratory evaluations 
A total of 4/25 patients (16%) developed ADA during the overall study period.  Limited data shows 
there 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 the 
paediatric GPA and MPA clinical trials. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
MabThera in paediatric population < 2 years of age in severe, active GPA or MPA. See section 4.2 for 
information on paediatric use. 
 
Clinical experience in pemphigus vulgaris 
 
PV Study 1 (Study ML22196) 
The efficacy and safety of MabThera in combination with short-term, low-dose glucocorticoid 
(prednisone) therapy were evaluated in newly diagnosed patients with moderate to severe pemphigus 
(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 prior 
therapies for pemphigus. In the PV population, 5 (13%) patients in the MabThera group and 3 (8%) 
patients in the standard prednisone group had moderate disease and 33 (87%) patients in the 
MabThera group and 33 (92%) patients in the standard-dose prednisone group had severe disease 
according to disease severity defined by Harman’s criteria. 
 
Patients were stratified by baseline disease severity (moderate or severe) and randomised 1:1 to 
receive either MabThera and low-dose prednisone or standard-dose prednisone.  Patients randomised 
to the MabThera group received an initial intravenous infusion of 1000 mg MabThera on Study Day 1 
in combination with 0.5 mg/kg/day oral prednisone tapered off over 3 months if they had moderate 
disease or 1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease, and a 
second intravenous infusion of 1000 mg on Study Day 15. Maintenance infusions of MabThera 
500 mg were administered at months 12 and 18. Patients randomised to the standard-dose prednisone 
group received an initial 1 mg/kg/day oral prednisone tapered off over 12 months if they had moderate 
disease or 1.5 mg/kg/day oral prednisone tapered off over 18 months if they had severe disease.  
Patients in the MabThera group who relapsed could receive an additional infusion of MabThera 
1000 mg in combination with reintroduced or escalated prednisone dose. Maintenance and relapse 
infusions were administered no sooner than 16 weeks following the previous infusion.  



50 

 
The primary objective for the study was complete remission (complete epithelialisation and absence of 
new and/or established lesions) at month 24 without the use of prednisone therapy for two months or 
more (CRoff for ≥2 months).  
 
PV Study 1 Results 
The study showed statistically significant results of MabThera 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 corticosteroid 
therapy for two months or more at month 24 (Intent-to-Treat Population - PV) 

 Rituximab + 
Prednisone 

N=38 

Prednisone 
N=36 

 
p-value a 95% CIb 

Number of responders      
(response rate [%]) 

34 (89.5%) 10 (27.8%) <0.0001 61.7% (38.4, 76.5) 

ap-value is from Fisher’s exact test with mid-p correction 
b 95% confidence interval is corrected Newcombe interval   

 

 
The number of rituximab plus low-dose prednisone patients off prednisone therapy or on minimal 
therapy (prednisone dose of 10 mg or less per day) compared to standard-dose prednisone patients 
over the 24-month treatment period shows a steroid-sparing effect of MabThera (Figure 4).  
 
Figure 4:  Number of patients who were off or on minimal corticosteroid (≤10mg/day) therapy 

over time 

 

 
Post-hoc retrospective laboratory evaluation 
A total of 19/34 (56%) patients with PV, who were treated with MabThera, tested positive for ADA 
antibodies by 18 months. The clinical relevance of ADA formation in MabThera-treated PV patients is 
unclear.  
 
PV Study 2 (Study WA29330) 
In a randomized, double-blind, double-dummy, active-comparator, multicenter study, the efficacy and 
safety of MabThera compared with mycophenolate mofetil (MMF) were evaluated in patients with 
moderate-to-severe PV receiving 60-120 mg/day oral prednisone or equivalent (1.0-1.5 mg/kg/day) at 
study entry and tapered to reach a dose of 60 or 80 mg/day by Day 1.  Patients had a confirmed 
diagnosis of PV within the previous 24 months and evidence of moderate-to-severe disease (defined as 
a total Pemphigus Disease Area Index, PDAI, activity score of ≥ 15).   



51 

One hundred and thirty-five patients were randomized to treatment with MabThera 1000 mg 
administered on Day 1, Day 15, Week 24 and Week 26 or oral MMF 2 g/day for 52 weeks in 
combination 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 MabThera 
compared with MMF in achieving sustained complete remission defined as achieving healing of 
lesions with no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or 
equivalent, and maintaining this response for at least 16 consecutive weeks, during the 52-week 
treatment period.  
 
PV Study 2 Results 
The study demonstrated the superiority of MabThera over MMF in combination with a tapering course 
of oral corticosteroids in achieving CRoff corticosteroid ≥ 16 weeks at Week 52 in PV patients (Table 
23).The majority of patients in the mITT population were newly diagnosed (74%) and 26% of patients 
had established disease (duration of illness ≥ 6 months and received prior treatment for PV).  
 
Table 23  Percentage of PV Patients Who Achieved Sustained Complete Remission Off 

Corticosteroid Therapy for 16 Weeks or More at Week 52 (Modified Intent-to-Treat 
Population) 

 MabThera 
(N=62) 

MMF 
(N=63) 

Difference (95% CI) p-value 

Number of responders 
(response rate [%]) 
 

Newly diagnosed patients 
 

Patients with established 
disease 

 

25 (40.3%) 
 
19 (39.6%)  
 
6 (42.9%) 

6 (9.5%) 
 
4 (9.1%)  
 
2 (10.5%) 

30.80% (14.70%, 45.15%) <0.0001 

MMF = Mycophenolate mofetil. CI = Confidence Interval.  
Newly diagnosed patients = duration of illness < 6 months or no prior treatment for PV.  
Patients with established disease = duration of illness ≥ 6 months and received prior treatment for 
PV.  
Cochran-Mantel-Haenszel test is used for p-value.  

 
The analysis of all secondary parameters (including cumulative oral corticosteroid dose, the total 
number 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 MabThera compared to MMF. 
Testing of secondary endpoints were controlled for multiplicity.  
 
Glucocorticoid exposure 
The cumulative oral corticosteroid dose was significantly lower in patients treated with MabThera.  
The median (min, max) cumulative prednisone dose at Week 52 was 2775 mg (450, 22180) in the 
MabThera group compared to 4005 mg (900, 19920) in the MMF group (p=0.0005).  
 
Disease flare 
The total number of disease flares was significantly lower in patients treated with MabThera compared 
to MMF (6 vs. 44, p<0.0001) and there were fewer patients who had at least one disease flare (8.1% 
vs. 41.3%). 
 



52 

Laboratory evaluations 
By week 52, a total of 20/63 (31.7%) (19 treatment-induced and 1 treatment-enhanced) MabThera -
treated PV patients tested positive for ADA.  There was no apparent negative impact of the presence 
of ADA on safety or efficacy in PV Study 2. 
 
5.2 Pharmacokinetic properties 
 
Adult Non-Hodgkin’s lymphoma 
 
Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple 
infusions of MabThera as a single agent or in combination with CHOP therapy (applied MabThera 
doses ranged from 100 to 500 mg/m2), the typical population estimates of nonspecific clearance (CL1), 
specific clearance (CL2) likely contributed by B cells or tumour burden, and central 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 MabThera was 22 days (range, 6.1 to 52 days). Baseline 
CD19-positive cell counts and size of measurable tumour lesions contributed to some of the variability 
in CL2 of MabThera in data from 161 patients given 375 mg/m2 as an intravenous infusion for 4 
weekly doses. Patients with higher CD19-positive cell counts or tumour lesions had a higher CL2. 
However, a large component of inter-individual variability remained for CL2 after correction for 
CD19-positive cell counts and tumour 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, were relatively small. Age, gender and WHO 
performance status had no effect on the pharmacokinetics of MabThera.  This analysis suggests that 
dose adjustment of MabThera with any of the tested covariates is not expected to result in a 
meaningful reduction in its pharmacokinetic variability. 
 
MabThera, administered as an intravenous infusion at a dose of 375 mg/m2 at weekly intervals for 4 
doses to 203 patients with NHL naive to MabThera, yielded a mean Cmax following the fourth infusion 
of 486 µg/mL (range, 77.5 to 996.6 µg/mL). Rituximab was detectable in the serum of patients 3 – 6 
months after completion of last treatment. 
 
Upon administration of MabThera at a dose of 375 mg/m2 as an intravenous infusion at weekly 
intervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusion, 
spanning from a mean of 243 µg/mL (range, 16 – 582 µg/mL) after the first infusion to 550 µg/mL 
(range, 171 – 1177 µg/mL) after the eighth infusion. 
 
The pharmacokinetic profile of MabThera when administered as 6 infusions of 375 mg/m2 in 
combination with 6 cycles of CHOP chemotherapy was similar to that seen with MabThera alone. 
 
Paediatric DLBCL/BL/BAL/BLL  
 
In the clinical trial studying paediatric DLBCL/BL/BAL/BLL, the PK was studied in a subset of 35 
patients aged 3 years and older. The PK was comparable between the two age groups (ε3 to <12 years 
vs. ε12 to <18 years). After two MabThera IV infusions of 375 mg/m2 in each of the two induction 
cycles (cycle 1 and 2) followed by one MabThera IV infusion of 375 mg/m2 in each of the 
consolidation cycles (cycle 3 and 4) the maximum concentration was highest after the fourth infusion 
(cycle 2) with a geometric mean of 347 g/mL followed by lower geometric mean maximum 
concentrations thereafter (Cycle 4: 247 g/mL). With this dose regimen, trough levels were sustained 
(geometric means: 41.8 µg/mL (pre-dose Cycle 2; after 1 cycle), 67.7 µg/mL (pre-dose Cycle 3, after 
2 cycles) and 58.5 µg/mL (pre-dose Cycle 4, after 3 cycles)). The median elimination half-life in 
paediatric patients aged 3 years and older was 26 days. 
 
The PK characteristics of MabThera in paediatric patients with DLBCL/BL/BAL/BLL were similar to 
what has been observed in adult NHL patients. 
 



53 

No PK data are available in the ≥ 6 months to < 3 years age group, however, population PK prediction 
supports comparable systemic exposure (AUC, Ctrough) in this age group compared to ≥ 3 years 
(Table 24). Smaller baseline tumor size is related to higher exposure due to lower time dependent 
clearance, however, systemic exposures impacted by different tumor sizes remain in the range of 
exposure that was 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 
 
MabThera was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to 
500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL 
patients. The mean Cmax (N=15) was 408 µg/mL (range, 97 – 764 µg/mL) after the fifth 500 mg/m2 
infusion and the mean terminal half-life was 32 days (range, 14 – 62 days). 
 
Rheumatoid arthritis  
 
Following two intravenous infusions of MabThera at a dose of 1000 mg, two weeks apart, the mean 
terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day 
(range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 l (range, 1.7 to 
7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic 
clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis 
revealed that BSA and gender were the most significant covariates to explain inter-individual 
variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume 
of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic 
differences are not considered to be clinically relevant and dose adjustment is not required. No 
pharmacokinetic data are available in patients with hepatic or renal impairment.  
 
The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg 
and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were 
dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first 
infusion ranged from 157 to 171 µg/mL for 2 x 500 mg dose and ranged from 298 to 341 µg/mL for 2 
x 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 terminal 
elimination half-life ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days for 
the 2 × 1000 mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared to 
the first infusion for both doses. 
 
The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg 
upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was 
170 to 175 µg/mL for 2 x 500 mg dose and 317 to 370 µg/mL for 2 x 1000 mg dose. Cmax following 
second infusion, was 207 µg/mL for the 2 x 500 mg dose and ranged from 377 to 386 µg/mL for the 2 
x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second 
course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 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 the 
same dosage regimen (2 x 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serum 
concentration of 369 µg/mL and a mean terminal half-life of 19.2 days. 



54 

 
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 
 
Adult Population 
 
Based on the population pharmacokinetic analysis of data in 97 patients with granulomatosis with 
polyangiitis and microscopic polyangiitis who received 375 mg/m2 MabThera once weekly for four 
doses, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days). 
Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726 L/day) 
and 4.50 L (range 2.25 to 7.39 L) respectively. Maximum concentration during the first 180 days 
(Cmax), minimum concentration at Day 180 (C180) and Cumulative area under the curve over 180 days 
(AUC180) were (median [range]) 372.6 (252.3-533.5) µg/mL, 2.1 (0-29.3) µg/mL and 10302 (3653-
21874)µg/mL*days, respectively. The PK parameters of rituximab in adult GPA and MPA patients 
appear similar to what has been observed in rheumatoid arthritis patients. 
 
Paediatric Population 
 
Based on the population pharmacokinetic analysis of 25 children (6-17 years old) with GPA and MPA 
who received 375 mg/m2 MabThera once weekly for four doses, the estimated median terminal 
elimination half-life was 22 days (range, 11 to 42 days). Rituximab mean clearance and volume of 
distribution were 0.221 L/day (range, 0. 0996 to 0.381 L/day) and 2.27 L (range 1.43 to 3.17 L) 
respectively. Maximum concentration during the first 180 days (Cmax), minimum concentration at Day 
180 (C180) and Cumulative area under the curve over 180  days (AUC180) were (median [range]) 
382.8 (270.6-513.6) µg/mL, 0.9 (0-17.7) µg/mL and 9787 (4838-20446) µg/mL*day, respectively.The 
PK parameters of rituximab in paediatric patients with GPA or MPA were similar to those in adults 
with GPA or MPA, once taking into account the BSA effect on clearance and volume of distribution 
parameters. 
 
Pemphigus vulgaris 
 
The PK parameters in adult PV patients receiving MabThera 1000 mg at Days 1, 15, 168, and 182 are 
summarized in Table 25. 
 
Table 25 Population PK in adult PV patients from PV Study 2  

Parameter Infusion Cycle 

 1st cycle of 1000 mg 
Day 1 and Day 15 

N=67 

2nd cycle of 1000 mg 
Day 168 and Day 182 

N=67 

Terminal Half-life (days) 
Median 
(Range) 

 
21.0 

(9.3-36.2) 

 
26.5 

(16.4-42.8) 
Clearance (L/day) 

Mean 
(Range) 

 
391 

(159-1510) 

 
247 

(128-454) 
Central Volume of 

Distribution (L) 
Mean 

(Range) 

 
3.52 

(2.48-5.22) 

 
3.52 

(2.48-5.22) 

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



55 

5.3 Preclinical safety data 
 
Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in 
cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of 
B cells in peripheral blood and in lymphoid tissue.  
 
Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to 
100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus 
due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid 
organs of the foetuses was observed, which persisted post natally and was accompanied by a decrease 
in IgG level in the newborn animals affected. B cell counts returned to normal in these animals 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 relevant 
for this molecule. No long-term animal studies have been performed to establish the carcinogenic 
potential of rituximab. 
Specific studies to determine the effects of rituximab on fertility have not been performed. In general 
toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or 
females were observed.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium citrate (E331) 
Polysorbate 80 (E433) 
Sodium chloride 
Sodium hydroxide (for pH adjustment) (E524) 
Hydrochloric acid (for pH adjustment) (E507) 
Water for injections 
 
6.2 Incompatibilities 
 
No incompatibilities between MabThera and polyvinyl chloride or polyethylene bags or infusion sets 
have been observed. 
 
6.3 Shelf life 
 
Unopened vial 
36 months 
 
Diluted medicinal product 
 
• After aseptic dilution in sodium chloride solution 
The prepared infusion solution of MabThera in 0.9% sodium chloride solution is physically and 
chemically stable for 30 days at 2 °C - 8 °C plus an additional 24 hours at ≤ 30 °C.  
 
• After aseptic dilution in D-glucose solution 
The prepared infusion solution of MabThera in 5% D-glucose solution is physically and chemically 
stable for 24 hours at 2 °C - 8 °C plus an additional 12 hours at room temperature. 
 
From a microbiological point of view, the prepared infusion solution should be used immediately. If 
not used immediately, in-use storage times and conditions prior to use are the responsibility of the user 
and would normally not be longer than 24 hours at 2 °C – 8 °C, unless dilution has taken place in 
controlled and validated aseptic conditions. 
 



56 

6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from 
light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
MabThera 100 mg concentrate for solution for infusion 
Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10 mL. Pack of 2 
vials. 
 
MabThera 500 mg concentrate for solution for infusion  
Clear Type I glass vials with butyl rubber stopper containing 500 mg of rituximab in 50 mL. Pack of 1 
vial. 
 
6.6 Special precautions for disposal and other handling 
 
MabThera is provided in sterile, preservative-free, non-pyrogenic, single use vials. 
 
Aseptically withdraw the necessary amount of MabThera, and dilute to a calculated concentration of 
1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 
9 mg/mL (0.9%) solution for injection or 5% D-Glucose in water. For mixing the solution, gently 
invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared 
solutions. Since the medicinal product does not contain any anti-microbial preservative or 
bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be 
inspected visually for particulate matter and discolouration prior to administration.  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
MabThera 100 mg concentrate for solution for infusion 
EU/1/98/067/001 
 
MabThera 500 mg concentrate for solution for infusion  
EU/1/98/067/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 2 June 1998  
Date of latest renewal: 2 June 2008 
 
 



57 

10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 



58 

1. NAME OF THE MEDICINAL PRODUCT 
 
MabThera 1400 mg solution for subcutaneous injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL contains 120 mg of rituximab. 
 
Each vial contains 1400 mg/11.7 mL rituximab. 
 
Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a 
glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and 
heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster 
ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including 
specific viral inactivation and removal procedures.  
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. 
 
Clear to opalescent, colourless to yellowish liquid with pH of 5.2 – 5.8 and osmolality of 300 - 400 
mOsmol/kg.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
MabThera is indicated in adults for Non-Hodgkin’s lymphoma (NHL):  
 
MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicular 
lymphoma in combination with chemotherapy.  
 
MabThera maintenance therapy is indicated for the treatment of follicular lymphoma patients 
responding to induction therapy.  
 
MabThera is indicated for the treatment of patients with CD20 positive diffuse large B cell 
non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, 
prednisolone) chemotherapy.  
 
4.2 Posology and method of administration 
 
MabThera should be administered under the close supervision of an experienced healthcare 
professional, and in an environment where full resuscitation facilities are immediately available (see 
section 4.4).  
 
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and 
diphenhydramine, should always be given before each administration of MabThera. 
 
Premedication with glucocorticoids should be considered if MabThera is not given in combination 
with glucocorticoid-containing chemotherapy.  
 



59 

Posology 
 
The recommended dose of MabThera subcutaneous formulation used for adult patients is a 
subcutaneous injection at a fixed dose of 1400 mg irrespective of the patient’s body surface area.  
 
Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full 
dose of MabThera by intravenous infusion, using MabThera intravenous formulation (see section 4.4). 
 
If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, 
they should continue the subsequent cycles with MabThera intravenous formulation until a full 
intravenous dose is successfully administered.  
Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or 
subsequent cycles of treatment. 
 
It is important to check the medicinal product labels to ensure that the appropriate formulation 
(intravenous or subcutaneous formulation) and strength is being given to the patient, as prescribed. 
 
MabThera subcutaneous formulation is not intended for intravenous administration and should be 
given via subcutaneous injection only. The 1400 mg strength is intended for subcutaneous use in non 
Hodgkin lymphoma (NHL) only. 
 
Follicular non-Hodgkin's lymphoma 
 
Combination therapy 
The recommended dose of MabThera in combination with chemotherapy for induction treatment of 
previously untreated or relapsed/ refractory patients with follicular lymphoma is: first cycle with 
MabThera intravenous formulation 375 mg/m2 body surface area, followed by subsequent cycles with 
MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle for up to 8cycles. 
 
MabThera should be administered on day 1 of each chemotherapy cycle, after administration of the 
glucocorticoid component of the chemotherapy if applicable. 
 
Maintenance therapy 

• Previously untreated follicular lymphoma 
The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment for 
patients with previously untreated follicular lymphoma who have responded to induction treatment is:  
1400 mg once every 2 months (starting 2 months after the last dose of induction therapy) until disease 
progression or for a maximum period of two years (12 administrations in total). 
 

• Relapsed/refractory follicular lymphoma 
The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment for 
patients with relapsed/refractory follicular lymphoma who have responded to induction treatment is: 
1400 mg 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 administrations in total).  
 
Diffuse large B cell non-Hodgkin's lymphoma 
 
MabThera should be used in combination with CHOP chemotherapy. The recommended dose is: first 
cycle, MabThera intravenous formulation: 375 mg/m2 body surface area, followed by subsequent 
cycles with MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle. In 
total: 8 cycles. 
 
MabThera is administered on day 1 of each chemotherapy cycle after intravenous infusion of the 
glucocorticoid component of CHOP. 
 
Safety and efficacy of MabThera have not been established in combination with other chemotherapies 
in diffuse large B cell non-Hodgkin’s lymphoma. 



60 

 
Dose adjustments during treatment 
 
No dose reductions of MabThera are recommended. When MabThera is given in combination with 
chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be 
applied (see section 4.8). 
 
Special populations 
 
Paediatric population 
The safety and efficacy of MabThera in children below 18 years has not been established. No data are 
available. 
 
Elderly 
No dose adjustment is required in elderly patients (aged >65 years).  
 
Method of administration 
 
Subcutaneous injections: 
MabThera 1400 mg subcutaneous formulation should be administered as subcutaneous injection only, 
over approximately 5 minutes. The hypodermic injection needle must only be attached to the syringe 
immediately prior to administration to avoid potential needle clogging. 
 
MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall and 
never into areas where the skin is red, bruised, tender, hard or areas where there are moles or scars. 
 
No data are available on performing the injection in other sites of the body, therefore injections should 
be restricted to the abdominal wall. 
 
During the treatment course with MabThera subcutaneous formulation, other medicinal products for 
subcutaneous administration should preferably be given at different sites. 
 
If an injection is interrupted it can be resumed at the same site or another location may be used, if 
appropriate. 
 
Intravenous infusion administration:  
The Summary of Product Characteristics (SmPC) of MabThera100 mg and 500 mg concentrate for 
solution for infusion should be referred to for information on dosing instructions and method of 
administration. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to murine proteins, hyaluronidase or to any of the other 
excipients listed in section 6.1.  
 
Active, severe infections (see section 4.4). 
 
Patients in a severely immunocompromised state. 
 
4.4 Special warnings and precautions for use 
 
Traceability 
In order to improve traceability of biological medicinal products, the tradename and batch number of 
the administered product should be clearly recorded. 
 



61 

The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation 
in the approved indications Treatment of non-Hodgkin’s lymphoma (strength 1400 mg) and Treatment 
of Chronic Lymphocytic Leukaemia (strength 1600 mg). For information related to the other 
indications, please refer to the SmPC of MabThera intravenous formulation.  
 
The use of MabThera subcutaneous formulation as monotherapy in patients with stage III-IV follicular 
lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy 
cannot be recommended as the safety of the once weekly subcutaneous administration has not been 
established. 
 
Progressive multifocal leukoencephalopathy 
 
Use of MabThera may be associated with an increased risk of progressive multifocal 
leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening 
neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing 
must be suspended until PML has been excluded. The clinician should evaluate the patient to 
determine if the symptoms are indicative of neurological dysfunction, and if so, whether these 
symptoms are possibly suggestive of PML. Consultation with a neurologist should be considered as 
clinically indicated. 
 
If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal 
fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.  
 
The physician should be particularly alert to symptoms suggestive of PML that the patient may not 
notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to 
inform their partner or caregivers about their treatment, since they may notice symptoms that the 
patient is not aware of. 
 
If a patient develops PML, the dosing of MabThera must be permanently discontinued.  
 
Following reconstitution of the immune system in immunocompromised patients with PML, 
stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and 
suspension of MabThera therapy may lead to similar stabilisation or improved outcome. 
 
Infusion/Administration-related reactions 
 
MabThera is associated with infusion/administration-related reactions, which may be related to release 
of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically 
indistinguishable from acute hypersensitivity reactions. 
 
This set of reactions which includes syndrome of cytokine release, tumor lysis syndrome and 
anaphylactic and hypersensitivity reactions are described below. They are not specifically related to 
the route of administration of MabThera and can be observed with both formulations. 
 
Severe infusion-related reactions with fatal outcome have been reported during post-marketing use of 
the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after 
starting the first MabThera intravenous infusion. They were characterized by pulmonary events and in 
some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, 
chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8). 
 
Severe cytokine release syndrome is characterised by severe dyspnea, often accompanied by 
bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This 
syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, 
hyperkalaemia, hypocalcaemia, hyperphosphaetemia, acute renal failure, elevated lactate 
dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute 
respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, 
visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating 



62 

the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour 
infiltration may be at greater risk of poor outcome and should be treated with increased caution. 
Patients who develop severe cytokine release syndrome should have their infusion interrupted 
immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial 
improvement of clinical symptoms may be followed by deterioration, these patients should be closely 
monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. 
Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in 
repeated severe cytokine release syndrome.  
 
Patients with a high tumour burden or with a high number (≥25 x 109/L) of circulating malignant cells, 
who may be at higher risk of especially severe cytokine release syndrome, should  be treated with 
extreme caution. These patients should be very closely monitored throughout the first infusion. 
Consideration should be given to the use of a reduced infusion rate for the first infusion in these 
patients or a split dosing over two days during the first cycle and any subsequent cycles if the 
lymphocyte count is still >25 x 109/L. 
 
Anaphylactic and other hypersensitivity reactions have been reported following the intravenous 
administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity 
reactions typically occur within minutes after starting infusion. 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 allergic reaction during administration of MabThera. 
Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine 
release syndrome (described above). Reactions attributed to hypersensitivity have been reported less 
frequently than those attributed to cytokine release. 
 
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary 
oedema and acute reversible thrombocytopenia. 
 
Since hypotension may occur during MabThera administration, consideration should be given to 
withholding anti-hypertensive medicines 12 hours prior to giving MabThera. 
 
Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with 
MabThera intravenous formulation (including cytokine release syndrome accompanied by 
hypotension and bronchospasm in 10 % of patients) see section 4.8. These symptoms are usually 
reversible with interruption of MabThera infusion and administration of an anti-pyretic, an 
antihistaminic, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if 
required. Please see cytokine release syndrome above for severe reactions. 
 
Administration related reactions have been observed in up to 50% of patients treated with MabThera 
subcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the 
subcutaneous injection consisted primarily of erythema pruritus, rash and injections site reactions such 
as pain, swelling and redness and were generally of mild or moderate (grade 1 or 2) and transient 
nature (see section 4.8). 
 
Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical 
trials.  Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see 
section 4.8). Some local cutaneous reactions occurred more than 24 hours after the MabThera 
subcutaneous administration. The majority of local cutaneous reactions seen following administration 
of MabThera subcutaneous formulation was mild or moderate and resolved without any specific 
treatment. 
 
Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full 
dose of MabThera by intravenous infusion, using MabThera intravenous formulation. The highest risk 
of experiencing an administration related reaction is generally observed at cycle one. Beginning the 



63 

therapy with MabThera intravenous infusion would allow a better handling of the administration 
reactions by slowing or stopping the intravenous infusion.  
 
If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, 
they should continue the subsequent cycles with MabThera intravenous formulation until a full 
intravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneous 
formulation can only occur at the second or subsequent cycles of treatment. 
 
As with the intravenous formulation, MabThera subcutaneous formulation should be administered in 
an environment where full resuscitation facilities are immediately available and under the close 
supervision of an experienced healthcare professional. Premedication consisting of an 
analgesic/antipyretic and an antihistamine should always be administered before each dose of 
MabThera subcutaneous formulation. Premedication with glucocorticoids should also be considered. 
 
Patients should be observed for at least 15 minutes following MabThera subcutaneous 
administration. A longer period may be appropriate in patients with an increased risk of 
hypersensitivity reactions. 
 
Patients should be instructed to contact their treating physician immediately if symptoms that are 
suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinal 
product administration. 
 
Cardiac disorders 
 
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or 
myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a 
history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. 
 
Haematological toxicities 
 
Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when 
considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L as 
clinical experience in this population is limited. The MabThera intravenous formulation has been used 
in 21 patients who underwent autologous bone marrow transplantation and other risk groups with a 
presumable reduced bone marrow function without inducing myelotoxicity. 
 
Regular full blood counts, including neutrophil and platelet counts, should be performed during 
MabThera therapy.  
 
Infections 
 
Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). 
MabThera 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 MabThera in patients with a history of 
recurring or chronic infections or with underlying conditions which may further predispose patients to 
serious infection (see section 4.8).  
 
Cases of hepatitis B reactivation have been reported in patients receiving the MabThera intravenous 
formulation including fulminant hepatitis with fatal outcome. The majority of these patients were also 
exposed to cytotoxic chemotherapy. Hepatitis B virus (HBV) screening should be performed in all 
patients before initiation of treatment with MabThera. At minimum this should include HBsAg-status 
and HBcAb-status. These can be complemented with other appropriate markers as per local 
guidelines. Patients with active hepatitis B disease should not be treated with MabThera. Patients with 
positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before 



64 

start of treatment and should be monitored and managed following local medical standards to prevent 
hepatitis B reactivation.  
 
Very rare cases of PML have been reported during post-marketing use of the MabThera intravenous 
formulation in NHL (see section 4.8). The majority of patients had received rituximab in combination 
with chemotherapy or as part of a hematopoietic stem cell transplant.  
 
Immunisation 
 
The safety of immunisation with live viral vaccines, following MabThera therapy has not been studied 
for NHL patients and vaccination with live virus vaccines is not recommended. Patients treated with 
MabThera may receive non-live vaccinations; however, with non-live vaccines response rates may be 
reduced. In a non-randomized study, patients with relapsed low-grade NHL who received the 
MabThera intravenous formulation as monotherapy when compared to healthy untreated controls had 
a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet 
Haemocyanin (KLH) neoantigen (4% vs. 69% when assessed for >2-fold increase in antibody titer).  
 
Mean pre-therapeutic antibody titers against a panel of antigens (Streptococcus pneumoniae, influenza 
A, mumps, rubella and varicella) were maintained for at least 6 months after treatment with 
MabThera.  
 
Skin reactions 
 
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). In case of such an event, 
with suspected relationship to MabThera, treatment should be permanently discontinued. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Currently, there are limited data on possible drug interactions with MabThera.  
 
Co-administration with MabThera did not appear to have an effect on the pharmacokinetics of 
fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and 
cyclophosphamide on the pharmacokinetics of MabThera. 
 
Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have 
allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal 
antibodies. 
 
4.6 Fertility, pregnancy and lactation 
 
Contraception in males and females 
 
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing 
potential must employ effective contraceptive methods during and for 12 months after treatment with 
MabThera. 
 
Pregnancy 
 
IgG immunoglobulins are known to cross the placental barrier. 
 
B-cell levels in human neonates following maternal exposure to MabThera have not been studied in 
clinical 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 to 
mothers exposed to MabThera during pregnancy. Similar effects have been observed in animal studies 
(see section 5.3).For these reasons MabThera should not be administered to pregnant women unless 
the possible benefit outweighs the potential risk. 



65 

 
Breast-feeding 
 
Whether rituximab is excreted in human milk is not known. However, because maternal IgG is 
excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should 
not breastfeed while treated with MabThera and for 12 months following MabThera treatment. 
 
Fertility 
 
Animal studies did not reveal deleterious effects of rituximab or recombinant human hyaluronidase 
(rHuPH20) on reproductive organs. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects of MabThera on the ability to drive and use machines have been performed, 
although the pharmacological activity and adverse reactions reported to date suggest that MabThera 
would have no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
The information provided in this section pertains to the use of MabThera in oncology.  
For information related to the autoimmune indications, please refer to the SmPC of MabThera 
intravenous formulation. 
 
Summary of the safety profile 
 
During the development programme, the safety profile of MabThera subcutaneous formulation was 
comparable to that of the intravenous formulation with the exception of local cutaneous reactions.  
Local cutaneous reactions, including injection site reactions were very common in patients receiving 
MabThera subcutaneous formulation. In the phase 3 SABRINA trial (BO22334), local cutaneous 
reaction were reported in up to 20% of patients receiving subcutaneous MabThera. The most common 
local cutaneous reactions in the Mabthera subcutaneous arm were injection erythema (13%), injection 
pain (7%) and injection site oedema (4%).Events seen following subcutaneous administration were 
mild or moderate, apart from one patient who reported a local cutaneous reaction of Grade 3 intensity 
(injection site rash) following the first MabThera subcutaneous administration (Cycle 2).  Local 
cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the 
first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with 
subsequent injections. 
 
Adverse reactions reported in MabThera subcutaneous formulation usage 
 
The risk of acute administration-related reactions associated with the subcutaneous formulation of 
MabThera was assessed in two open-label trials involving patients with follicular lymphoma during 
induction and maintenance (SABRINA/BO22334) and during maintenance only 
(SparkThera/BP22333). InSABRINA, severe administration-related reactions (grade≥3) were reported 
in two patients (2%) following administration of MabThera subcutaneous formulation. These events 
were Grade 3 injection site rash and dry mouth. InSparkThera, no severe administration-related 
reactions were reported. 
 
Adverse reactions reported in MabThera intravenous formulation usage 
 
Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia 
 
The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data from 
patients from clinical trials and from post-marketing surveillance. These patients were treated either 
with MabThera monotherapy (as induction treatment or maintenance treatment following induction 
treatment) or in combination with chemotherapy.  



66 

 
The most frequently observed adverse reactions (ADRs) in patients receiving MabThera were 
infusion-related reactions which occurred in the majority of patients during the first infusion. The 
incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less 
than 1 % after eight doses of MabThera. 
  
Infectious events (predominantly bacterial and viral) occurred in approximately 30-55 % of patients 
during clinical trials in patients with NHL and in 30-50 % of patients during clinical trial in patients 
with CLL. 
 
The most frequent reported or observed serious adverse reactions were: 
• Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), see 

section 4.4. 
• Infections, see section 4.4. 
• Cardiovascular disorders, see section 4.4. 
 
Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.). 
 
The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are 
summarised in Table 1. Frequencies are defined as very common (≥ 1/10), common  (≥ 1/100 to 
< 1/10), uncommon  (≥  1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) and 
not known (cannot be estimated from the available data). Within each frequency grouping, undesirable 
effects are presented in order of decreasing seriousness. 
 
The ADRs identified only during post-marketing surveillance, and for which a frequency could not be 
estimated, are listed under “not known”. 
 
Tabulated list of adverse reactions 
 
Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients 

with NHL and CLL disease treated with MabThera monotherapy/maintenance or in 
combination with chemotherapy  

MedDRA 
System 

Organ Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

Infections 
and 
infestations 

bacterial 
infections, 
viral 
infections, 
+bronchitis  
 

sepsis, 
+pneumonia, 
+febrile 
infection, 
+herpes zoster, 
+respiratory 
tract infection, 
fungal 
infections, 
infections of 
unknown 
aetiology, 
+acute 
bronchitis, 
+sinusitis, 
hepatitis B1  

 serious 
viral 
infection2 

  

Blood and 
lymphatic 
system 
disorders 

neutropenia, 
leucopenia, 
+febrile 
neutropenia, 
+thrombocytop
enia 
 

anaemia,  
+pancytopenia, 
+granulocytopen
ia 

coagulation 
disorders, 
aplastic 
anaemia, 
haemolytic 
anaemia, 
lymphadenopat
hy 

 transient 
increase in 
serum IgM 
levels3 

late 
neutropenia3 



67 

MedDRA 
System 

Organ Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

Immune 
system 
disorders 

infusion 
related 
reactions4, 
angioedema 

hypersensitivity  anaphylaxi
s 

tumour lysis 
syndrome, 
cytokine 
release 
syndrome4, 
serum sickness 

infusion-related 
acute reversible 
thrombocytopen
ia 4 

Metabolism 
and nutrition 
disorders 

 hyperglycaemia
, weight 
decrease, 
peripheral 
oedema, face 
oedema, 
increased LDH, 
hypocalcaemia 

    

Psychiatric 
disorders 

  depression, 
nervousness, 

   

Nervous 
system 
disorders 

 paraesthesia, 
hypoaesthesia, 
agitation, 
insomnia, 
vasodilatation, 
dizziness, 
anxiety 

dysgeusia  peripheral 
neuropathy, 
facial nerve 
palsy5 

cranial 
neuropathy, 
loss of other 
senses5 

Eye 
disorders 

 lacrimation 
disorder, 
conjunctivitis 

  severe vision 
loss5 

 

Ear and 
labyrinth 
disorders 

 tinnitus, ear 
pain 

   hearing loss5 

Cardiac 
disorders 

 +myocardial 
infarction4 and 6, 
arrhythmia, 
+atrial 
fibrillation, 
tachycardia, 
+cardiac 
disorder 

+left 
ventricular 
failure, 
+supraventricul
ar tachycardia,  
+ventricular 
tachycardia,  
+angina,  
+myocardial 
ischaemia, 
bradycardia 

severe 
cardiac 
disorders 4 
and 6 

heart failure4 
and 6 

 

Vascular 
disorders 

 hypertension, 
orthostatic 
hypotension, 
hypotension  

  vasculitis 
(predominately 
cutaneous), 
leukocytoclasti
c vasculitis 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Bronchospasm4, 
respiratory 
disease, chest 
pain, dyspnoea, 
increased 
cough, rhinitis 

asthma, 
bronchiolitis 
obliterans, 
lung disorder, 
hypoxia 

interstitial 
lung 
disease7 

respiratory 
failure4, 
 

lung infiltration,  

Gastrointesti
nal disorders 

nausea  vomiting , 
diarrhoea, 
abdominal pain, 
dysphagia, 
stomatitis, 
constipation, 
dyspepsia, 
anorexia, throat 
irritation 

abdominal 
enlargement 

 gastro-intestina
l perforation7 

 



68 

MedDRA 
System 

Organ Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

Skin and 
subcutaneou
s tissue 
disorders 

pruritis, rash, 
+alopecia  

urticaria, 
sweating, night 
sweats, +skin 
disorder 

  severe bullous 
skin reactions, 
Stevens-Johns
on Syndrome, 
toxic 
epidermal 
necrolysis 
(Lyell’s 
Syndrome) 7 

 

Musculoskel
etal, 
connective 
tissue 
disorders 

 hypertonia, 
myalgia, 
arthralgia, back 
pain, neck pain, 
pain 

    

Renal and 
urinary 
disorders 

    renal failure4  

General 
disorders 
and 
administrati
on site 
conditions 

fever , chills, 
asthenia, 
headache  

tumour pain, 
flushing, 
malaise, cold 
syndrome, 
+fatigue, 
+shivering,  
+multi-organ 
failure4 

infusion site 
pain 

   

Investigation
s 

decreased IgG 
levels 

     

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked 
with "+" where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria) reactions.  Only 
the highest frequency observed in the trials is reported 
1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 
2 see also section infection below  
3 see also section haematologic adverse reactions below 
4 see also section infusion-related reactions below. Rarely fatal cases reported 
5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of 

MabThera therapy 
6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated 

with infusion-related reactions 
7 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 MabThera-arms compared to control arms: 
haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia. 
 
Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50 % of 
patients in clinical trials involving MabThera intravenous formulation, and were predominantly seen 
during the first infusion, usually in the first one to two hours. These symptoms mainly comprised 
fever, chills and rigors. Other symptoms 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-related reactions (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 cardiac 
conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, 
myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis 
syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or 
unknown frequencies. The incidence of infusion-related symptoms decreased substantially with 
subsequent intravenous infusions and is <1% of patients by the eighth cycle of MabThera (containing) 
treatment.  
 



69 

Description of selected adverse reactions 
 
Infections  
MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreased 
serum immunoglobulins only in a minority of patients.  
 
Localized candida infections as well as Herpes zoster were reported at a higher incidence in the 
MabThera-containing arm of randomized studies. Severe infections were reported in about 4% of 
patients treated with MabThera monotherapy. Higher frequencies of infections overall, including 
grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when 
compared to observation. There was no cumulative toxicity in terms of infections reported over a 
2-year treatment period. In addition, other serious viral infections either new, reactivated or 
exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of 
patients had received MabThera in combination with chemotherapy or as part of a hematopoietic stem 
cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses 
(Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (PML) and hepatitis C 
virus. Cases of fatal PML that occurred after disease progression and retreatment have also been 
reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which 
were in patients receiving MabThera in combination with cytotoxic chemotherapy. Progression of 
Kaposi’s sarcoma has been observed in MabThera-exposed patients with pre-existing Kaposi’s 
sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV 
positive. 
 
Haematologic adverse reactions  
In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities 
occurred 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 
MabThera maintenance treatment for up to 2 years, leucopoenia (5% vs. 2%, grade 3/4) and 
neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to 
observation. The incidence of thrombocytopenia was low (<1 %, grade 3/4) and was not different 
between treatment arms. During the treatment course in studies with MabThera in combination with 
chemotherapy, grade 3/4 leucopoenia (R-CHOP 88% vs. CHOP 79%), neutropenia (R-CVP 24% vs. 
CVP 14%; R-CHOP 97% vs. CHOP 88%), were usually reported with higher frequencies when 
compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated 
with MabThera and chemotherapy was not associated with a higher incidence of infections and 
infestations compared to patients treated with chemotherapy alone. There were no differences reported 
for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the 
last infusion of MabThera were reported.  
 
In studies of MabThera in patients with Waldenstrom’s macroglobulinaemia, transient increases in 
serum IgM levels have been observed following treatment initiation, which may be associated with 
hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline 
level within 4 months. 
 
Cardiovascular adverse reactions 
Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% of 
patients with the most frequently reported events being hypotension and hypertension. Cases of grade 
3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during 
infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders 
was comparable between patients treated with MabThera and observation. Cardiac events were 
reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular 
failure, myocardial ischemia) in 3% of patients treated with MabThera compared to <1% on 
observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of 
grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia 
and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the 
CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera 
infusion or were associated with predisposing conditions such as fever, infection, acute myocardial 



70 

infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP 
and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart 
failure, myocardial disease and manifestations of coronary artery disease.  
 
Respiratory system 
Cases of interstitial lung disease, some with fatal outcome have been reported. 
 
Neurologic disorders  
During the treatment period (induction treatment phase comprising of R-CHOP for at most eight 
cycles), four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced 
thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference 
between the treatment groups in the incidence of other thromboembolic events. In contrast, three 
patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the 
follow-up period.   
 
Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior 
leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual 
disturbance, headache, seizures and altered mental status, with or without associated hypertension. A 
diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognized 
risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, 
immunosuppressive therapy and/or chemotherapy. 
 
Gastrointestinal disorders 
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving 
MabThera for treatment of Non-Hodgkin’s lymphoma (NHL). In the majority of these cases, 
MabThera was administered with chemotherapy.  
 
IgG levels 
In the clinical trial evaluating MabThera maintenance treatment in relapsed/refractory follicular 
lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction 
treatment in both the observation and the MabThera groups. In the observation group, the median IgG 
level subsequently increased to above the LLN, but remained constant in the MabThera group. The 
proportion of patients with IgG levels below the LLN was about 60% in the MabThera group 
throughout the 2 year treatment period, while it decreased in the observation group (36% after 
2 years). 
 
Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell Syndrome) and Stevens-Johnson syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Patient subpopulations - MabThera monotherapy 
Elderly (≥ 65 years):  
The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared to 
younger patients (<65 years).  
 
Bulky disease: 
There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients 
without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in these 
two groups. 
 
Re-treatment: 
The percentage of patients reporting ADRs upon re-treatment with further courses of MabThera was 
similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 
ADRs). 
 



71 

Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Limited experience with doses higher than the approved dose of intravenous MabThera formulation is 
available from clinical trials in humans. The highest intravenous dose of MabThera tested in humans 
to date is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. No additional 
safety signals were identified. 
Patients who experience overdose should have immediate interruption of their infusion and be closely 
monitored. 
 
Three patients in the MabThera subcutaneous formulation trial SABRINA (BO22334) were 
inadvertently administered subcutaneous formulation through the intravenous route up to a maximum 
rituximab dose of 2780 mg with no untoward effect.  
Patients who experience overdose or medication error should be closely monitored. 
 
In the post-marketing setting five cases of MabThera overdose have been reported. Three cases had no 
reported adverse event. The two adverse events that were reported were flu-like symptoms, with a 
dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02 
 
MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an 
enzyme used to increase the dispersion and absorption of co-administered substances when 
administered subcutaneously. 
 
Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated 
phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95 % of all 
B cell non-Hodgkin’s lymphomas.  
 
CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, 
pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon 
antibody binding and is not shed from the cell surface. CD20 does not circulate in the plasma 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 can 
recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated 
cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and 
antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the 
surface of granulocytes, macrophages and NK cells. Rituximab binding to CD 20 antigen on B 
lymphocytes has also been demonstrated to induce cell death via apoptosis. 
 
Peripheral B cell counts declined below normal following completion of the first dose of MabThera. In 
patients treated for hematological malignancies, B cell recovery began within 6 months of treatment 
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 months post-induction 
therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


72 

observed following two infusions of 1000 mg MabThera separated by a 14 day interval. Peripheral 
blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the 
majority of patients by week 40, whether MabThera was administered as monotherapy or in 
combination with methotrexate. 
 
Clinical experience of MabThera subcutaneous formulation in Non-Hodgkin’s lymphoma 
 
The clinical experience of MabThera subcutaneous formulation in Non-Hodgkin’s lymphoma is based 
on data from a phase III clinical trial (SABRINA BO22334) in patients with follicular lymphoma (FL) 
and a phase Ib dose-finding/dose-confirmation trial (SparkThera BP22333) in patients with FL. 
Results from trial BP22333 are presented in section 5.2. 
 
Trial BO22334 (SABRINA) 
A two-stage phase III, international, multi-centre, randomised, controlled, open-label trial was 
conducted in patients with previously untreated follicular lymphoma, to investigate the non-inferiority 
of the pharmacokinetic profile, together with efficacy and safety of MabThera subcutaneous 
formulation in combination with CHOP or CVP versus MabThera intravenous formulation in 
combination with CHOP or CVP.  
 
The objective of the first stage was to establish the rituximab subcutaneous dose that resulted in 
comparable MabThera subcutaneous formulation serum Ctrough levels compared with MabThera 
intravenous formulation, when given as part of induction treatment every 3 weeks (see section 5.2). 
Stage 1 enrolled previously untreated patients (n=127) CD20-positive, Follicular Lymphoma (FL) 
Grade 1, 2 or 3a. 
 
The objective of stage 2 was to provide additional efficacy and safety data for subcutaneous rituximab 
compared with rituximab intravenous using the 1400 mg subcutaneous dose established in stage 1.  
Previously untreated patients with CD20-positive, Follicular Lymphoma Grade 1, 2 or 3a (n=283) 
were enrolled in the stage 2. 
 
The overall trial design was identical among both stages and patients were randomized into the 
following two treatment groups: 
 
• MabThera subcutaneous formulation (n= 205): first cycle MabThera intravenous formulation 

plus 7 cycles of MabThera subcutaneous formulation in combination with up to 8 cycles of 
CHOP or CVP chemotherapy administered every 3 weeks. 
MabThera intravenous formulation was used at the standard dose of 375 mg/m2 body surface 
area. 
MabThera subcutaneous formulation was given at a fixed dose of 1400 mg. 
Patients achieving at least partial response (PR) were entered on the MabThera subcutaneous 

 formulation maintenance therapy once every 8 weeks for 24 months. 
 

• MabThera intravenous formulation (n= 205): 8 cycles of MabThera intravenous formulation in 
combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks.  
MabThera intravenous formulation was used at the standard dose of 375 mg/m2. 
Patients achieving at least PR were entered on MabThera intravenous formulation maintenance 
therapy once every 8 weeks for 24 months. 

 
Key efficacy results for the pooled analysis of 410 patients in SABRINA stages 1 and 2 are shown in 
table 2. 
 



73 

Table 2 Efficacy results for SABRINA (BO22334) (Intent to Treat Population) 
 Pooled Stages 1 & 2 

N = 410 

Rituximab 
intravenous 
formulation 

(n = 205) 

Rituximab 
subcutaneous 
formulation 

(n = 205) 

ORR a 
Point estimate 84.9% (n = 174) 84.4% (n = 173) 

95% CI [79.2%, 89.5%] [78.7%, 89.1%] 

CRR 
Point estimate 31.7% (n = 65) 32.2% (n = 66) 

95% CI [25.4%, 38.6%] [25.9%, 39.1%] 

PFSb 
Proportion with PFS event 34.6% (n = 71 ) 31.7% ( n = 65) 

Hazard ratio (95% CI) 0.90 [0.64%, 1.26%] 

ORR – Overall Response Rate 
CRR – Complete Response Rate 
PFS – Progression-Free Survival (proportion with event, disease progression/relapse or death from any cause) 
a – at end of Induction 
b – at time of final analysis (median follow-up 58 months)  
 
Exploratory analyses showed response rates among BSA, chemotherapy and gender subgroups were 
not notably different from the ITT population. 
 
Immunogenicity 
Data from the development programme of MabThera subcutaneous formulation indicate that the 
formation of anti-rituximab antibodies after subcutaneous administration is comparable with that 
observed after intravenous administration. In the SABRINA trial (BO22334) the incidence of 
treatment-induced/enhanced anti-rituximab antibodies was low and similar in the intravenous and 
subcutaneous groups (1.9% vs. 2%, respectively).  The incidence of treatment-induced/enhanced 
anti-rHuPH20 antibodies was 8% in the intravenous group compared with 15% in the subcutaneous 
group, and none of the patients who tested positive for anti-rHuPH20 antibodies tested positive for 
neutralizing antibodies.   
 
The overall proportion of patients found to have anti-rHuPH20 antibodies remained generally constant 
over the follow-up period in both cohorts. The clinical relevance of the development of anti-rituximab 
antibodies or anti-rHuPH20 antibodies after treatment with MabThera subcutaneous formulation is not 
known. 
There was no apparent impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety 
or efficacy. 
 
Clinical experience of MabThera concentrate for solution for infusion in Non-Hodgkin’s lymphoma  
 
Follicular lymphoma 
 
Initial treatment in combination with chemotherapy 
 



74 

In an open-label randomised trial, a total of 322 previously untreated patients with follicular 
lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2, 
vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 
1 -5) every 3 weeks for 8 cycles or MabThera 375 mg/m2 in combination with CVP (R-CVP). 
MabThera 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 of patients 
was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to 
treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with 
a tumour response (CR, CRu, PR) was significantly higher (p< 0.0001 Chi-Square test) in the R-CVP 
group (80.9 %) than the CVP group (57.2 %). Treatment with R-CVP significantly prolonged the time 
to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively (p 
< 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and 
was 13.5 months in the CVP group (p < 0.0001, log-rank test).  
 
The difference between the treatment groups with respect to overall survival showed a significant 
clinical difference (p=0.029, log-rank test stratified by center): survival rates at 53 months were 
80.9 % for patients in the R-CVP group compared to 71.1 % for patients in the CVP group. 
 
Results from three other randomized trials using MabThera in combination with chemotherapy 
regimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant 
improvements in response rates, time-dependent parameters as well as in overall survival. Key results 
from all four trials are summarized in table 3.  
 
Table 3 Summary of key results from four phase III randomized trials evaluating the benefit 

of MabThera with different chemotherapy regimens in follicular lymphoma 

Trial 
Treatment, 

N 

Median 
FU,  
months 

ORR, % CR, % 

Median 
TTF/PFS/ EFS 
mo 

OS 
rates, 
% 

M39021 
CVP, 159 
R-CVP, 162 53 

57 
81 

10 
41 

Median TTP: 
14.7 
33.6 

P<0.0001 

53-months  
71.1 
80.9 

p=0.029 

GLSG’00 
CHOP, 205 
R-CHOP, 223 

18 
90 
96 

17 
20 

Median TTF: 2.6 
years 

Not reached 
p < 0.001 

18-months 
90 
95 

p = 0.016 

OSHO-39 
MCP, 96 
R-MCP, 105 

47 
75 
92 

25  
50 

Median PFS: 28.8 
Not reached 
p < 0.0001 

48-months 
74  
87  

p = 0.0096 

FL2000 

CHVP-IFN, 
183 
R-CHVP-IFN, 
175 

42 
85  
94 

49 
76 

Median EFS: 36  
Not reached 
p < 0.0001 

42-months 
84  
91 

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 
 



75 

Maintenance therapy 
 
Previously untreated follicular lymphoma  
In a prospective, open label, international, multi-center, phase III trial 1193 patients with previously 
untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP 
(n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1078 patients responded 
to induction therapy, of which 1018 were randomized to MabThera maintenance therapy (n=505) or 
observation (n=513). The two treatment groups were well balanced with regards to baseline 
characteristics and disease status. MabThera maintenance treatment consisted of a single infusion of 
MabThera at 375 mg/m2 body surface area given every 2 months until disease progression or for a 
maximum period of two years.  
 
The pre-specified primary analysis was conducted at a median observation time of 25 months from 
randomization, maintenance therapy with MabThera resulted in a clinically relevant and statistically 
significant improvement in the primary endpoint of investigator assessed progression-free survival 
(PFS) as compared to observation in patients with previously untreated follicular lymphoma (Table 4).  
 
Significant benefit from maintenance treatment with MabThera was also seen for the secondary 
endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next 
chemotherapy (TNCT) and overall response rate (ORR) in the primary analysis (Table 4).  
 
Data from extended follow-up of patients in the study (median follow-up 9 years) confirmed the long-
term benefit of MabThera maintenance therapy in terms of PFS, EFS, TNLT and TNCT (Table 4). 
 



76 

Table 4 Overview of efficacy results for MabThera maintenance vs. observation at the 
protocol-defined primary analysis and after 9 years median follow-up (final 
analysis) 

 Primary analysis 
(median FU: 25 months) 

Final analysis 
(median FU: 9.0 years) 

Observation 
N=513 

MabThera 
N=505 

Observation 
N=513 

MabThera 
N=505 

Primary efficacy     
Progression-free survival (median) NR NR 4.06 years 10.49 years 
log-rank p value <0.0001 <0.0001 
hazard ratio (95% CI) 
risk reduction 

0.50 (0.39, 0.64) 
50% 

0.61 (0.52, 0.73) 
39% 

Secondary efficacy     
Overall survival (median) NR NR NR NR 
log-rank p value 0.7246 0.7948 
hazard ratio (95% CI) 
risk reduction 

0.89 (0.45, 1.74) 
11% 

1.04 (0.77, 1.40) 
-6% 

Event-free survival (median) 38 months NR 4.04 years 9.25 years 
log-rank p value <0.0001 <0.0001 
hazard ratio (95% CI) 
risk reduction  

0.54 (0.43, 0.69) 
46% 

0.64 (0.54, 0.76) 
36% 

TNLT (median) NR NR 6.11 years NR 
log-rank p value 0.0003 <0.0001 
hazard ratio (95% CI) 
risk reduction  

0.61 (0.46, 0.80) 
39% 

0.66 (0.55, 0.78) 
34% 

TNCT (median) NR NR 9.32 years NR 
log-rank p value 0.0011 0.0004 
hazard ratio (95% CI) 
risk reduction  

0.60 (0.44, 0.82) 
40% 

0.71 (0.59, 0.86) 
39% 

Overall response rate* 55% 74% 61% 79% 
chi-squared test p value <0.0001 <0.0001 
odds 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 <0.0001 
odds ratio (95% CI) 2.21 (1.65, 2.94) 2.34 (1.80, 3.03)  

* at end of maintenance/observation; final analysis results based on median follow-up of 73 months.  
FU: follow-up; NR: not reached at time of clinical cut off, TNCT: time to next chemotherapy treatment; TNLT: time to next 
anti lymphoma treatment. 
 
MabThera maintenance treatment provided consistent benefit in all predefined subgroups tested: 
gender (male, female), age (< 60 years, >= 60 years), FLIPI score (<=1, 2 or >= 3), induction therapy 
(R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment 
(CR/CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less 
pronounced effect in elderly patients (> 70 years of age), however sample sizes were small. 
 
Relapsed/Refractory follicular lymphoma  
In a prospective, open label, international, multi-centre, phase III trial, 465 patients with 
relapsed/refractory follicular lymphoma were randomised in a first step to induction therapy with 
either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or MabThera plus 
CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard to baseline 
characteristics and disease status. A total of 334 patients achieving a complete or partial remission 
following induction therapy were randomised in a second step to MabThera maintenance therapy 
(n=167) or observation (n=167). MabThera maintenance treatment consisted of a single infusion of 
MabThera at 375 mg/m2 body surface area given every 3 months until disease progression or for a 
maximum period of two years.  
 



77 

The final efficacy analysis included all patients randomized to both parts of the trial. After a median 
observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly 
improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to 
CHOP (see Table 5). 
 
Table 5 Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months 

median observation time)  
 CHOP R-CHOP p-value Risk Reduction1) 

Primary efficacy      
ORR2) 74 % 87 % 0.0003 Na 

CR2) 16 % 29 % 0.0005 Na 
PR2) 58 % 58 % 0.9449 Na 

1) Estimates were calculated by hazard ratios 
2) Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend 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 randomized to the maintenance phase of the trial, the median observation time was 28 
months from maintenance randomisation. Maintenance treatment with MabThera led to a clinically 
relevant and statistically significant improvement in the primary endpoint, PFS, (time from 
maintenance randomisation to relapse, disease progression or death) when compared to observation 
alone (p< 0.0001 log-rank test).The median PFS was 42.2 months in the MabThera maintenance arm 
compared to 14.3 months in the observation arm. Using a cox regression analysis, the risk of 
experiencing progressive disease or death was reduced by 61 % with MabThera maintenance 
treatment when compared to observation (95 % CI; 45 %-72 %). Kaplan-Meier estimated 
progression-free rates at 12 months were 78 % in the MabThera maintenance group vs. 57 % in the 
observation group. An analysis of overall survival confirmed the significant benefit of MabThera 
maintenance over observation (p=0.0039 log-rank test). MabThera maintenance treatment reduced the 
risk of death by 56 % (95 % CI; 22 %-75 %). 
 



78 

Table 6 Maintenance phase: overview of efficacy results MabThera vs. observation (28 
months median observation time)  

Efficacy Parameter Kaplan-Meier Estimate of  
Median Time to Event (Months) 

Risk 
Reduction 

Observation 
(N = 167) 

MabThera 
(N=167) 

Log-Rank  
p value 

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

Overall survival  NR NR 0.0039 56 % 
     

Time to new lymphoma 
treatment 

20.1 38.8 < 0.0001 50 % 

     
Disease-free survivala 
 

16.5 53.7 0.0003 67 % 

Subgroup analysis     
PFS 

CHOP 
R-CHOP 

CR 
PR 

 
 
OS 

CHOP 
R-CHOP 

 

 
11.6 
22.1 
14.3 
14.3 

 
 
 

NR 
NR 

 
37.5 
51.9 
52.8 
37.8 

 
 
 

NR 
NR 

 
< 0.0001 
0.0071 
 0.0008 

< 0.0001 
 
 
 

0.0348 
0.0482 

 
71 % 
46 % 
64 % 
54 % 

 
 
 

55 % 
56 % 

NR: not reached; a: only applicable to patients achieving a CR 
 
The benefit of MabThera maintenance treatment was confirmed in all subgroups analysed, regardless 
of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) 
(table 6). MabThera maintenance treatment significantly prolonged median PFS in patients responding 
to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p< 0.0001) as well as in those 
responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). Although 
subgroups were small, MabThera maintenance treatment provided a significant benefit 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.  
 
Diffuse large B cell non-Hodgkin’s lymphoma 
 
In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 
years) with diffuse large B cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 
750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and 
prednisolone 40 mg/m2/day on days 1-5) every 3 weeks for eight cycles, or MabThera 375 mg/m2 plus 
CHOP (R-CHOP). MabThera was administered on the first day of the treatment cycle.  
 
The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a 
median follow-up duration of approximately 31 months. The two treatment groups were well balanced 
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 in the 
duration of event-free survival (the primary efficacy parameter; where events were death, relapse or 
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 arm 
compared to 13 months in the CHOP arm, representing a risk reduction of 41 %. At 24 months, 
estimates for overall survival were 68.2 % in the R-CHOP arm compared to 57.4 % in the CHOP arm. 
A subsequent analysis of the duration of overall survival, carried out with a median follow-up duration 



79 

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-free 
survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The 
complete 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 all patients 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 for event-free survival and overall survival (R-CHOP compared with CHOP) were less than 
0.83 and 0.95 respectively. R-CHOP was associated with improvements in outcome for both high- and 
low-risk patients according to age adjusted IPI. 
 
Clinical laboratory findings  
 
Of 67 patients evaluated for HAMA, no responses were noted. Of 356 patients evaluated for ADA, 
1.1 % (4 patients) were positive. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
rituximab in all subsets of the paediatric population with follicular lymphoma. See Section 4.2 for 
information on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Rituximab pharmacokinetics following single dose administration of MabThera subcutaneous 
375 mg/m2, 625 mg/ m2 and 800 mg/ m2 were compared with MabThera intravenous 375 mg/ m2 in 
FL patients. Following subcutaneous administration, the absorption of rituximab is slow, reaching 
maximal concentrations about 3 days after administration. Based on popPK analysis an absolute 
bioavailability of 71% was estimated. Rituximab exposure increased dose proportional over the 
375 mg/m2 to 800 mg/m2 subcutaneous dose range. Pharmacokinetic parameters such as clearance, 
distribution volume, and elimination half-life were comparable for both formulations. 
 
Trial BP22333 (SparkThera) 
A two-stage phase Ib trial to investigate the pharmacokinetics, safety and tolerability of MabThera 
subcutaneous formulation in patients with follicular lymphoma (FL) as part of maintenance treatment. 
In stage 2, MabThera subcutaneous formulation at a fixed dose of 1400 mg was administered as 
subcutaneous injection during maintenance treatment, after at least one cycle of MabThera intravenous 
formulation to FL patients who had previously responded to MabThera intravenous formulation in 
induction. 
 
The comparison of predicted median Cmax data for MabThera subcutaneous formulation and 
intravenous formulation are summarized in Table 7.   
 
Table 7:  Trial BP22333 (SparkThera): Absorption - Pharmacokinetic parameters of MabThera 
SC compared to MabThera IV 

 MabThera 
subcutaneous 

MabThera 
intravenous 

Predicted median Cmax 
(q2m) µg/mL 

201 209 

Predicted median Cmax 
(q3m) µg/mL 

189  184 

 



80 

The median Tmax in the MabThera subcutaneous formulation was approximately 3 days as compared to 
the Tmax occuring at or close to the end of the infusion for the intravenous formulation. 
 
Trial BO22334 (SABRINA) 
MabThera subcutaneous formulation at a fixed dose of 1400 mg was administered for 6 cycles 
subcutaneously during induction at 3-weekly intervals, following the first cycle of MabThera 
intravenous formulation, in previously untreated FL patients in combination with chemotherapy. The 
serum rituximab Cmax at cycle 7 was similar between the two treatment arms, with geometric mean 
(CV%) values of 250.63 (19.01) μg/mL and 236.82 (29.41) μg/mL for the intravenous and the 
subcutaneous formulations respectively, with the resulting geometric mean ratio (Cmax, SC/Cmax, IV) of 
0.941 (90% CI: 0.872, 1.015).  
 
Distribution/Elimination 
 
Geometric mean Ctrough and geometric mean AUCτ from the BP22333 and BO22334 trials are 
summarized in Table 8. 
 
Table 8: Distribution/Elimination - Pharmacokinetic parameters of MabThera subcutaneous 
compared to MabThera intravenous 

Trial BP22333 (SparkThera) 
 Geometric 

mean Ctrough 
(q2m) µg/mL  

Geometric 
mean Ctrough 
(q3m) µg/mL 

Geometric 
mean AUCτ 
cycle 2 (q2m) 

µg.day/mL 

Geometric 
mean AUCτ 
cycle 2 (q3m) 

µg.day/mL 
MabThera 
subcutaneous 
formulation 

32.2 12.1 5430 5320 

MabThera 
intravenous 
formulation 

25.9  10.9  4012 3947 

Trial BO22334 (SABRINA) 
 Geometric mean 

Ctrough values at pre-dose cycle 8 
µg/mL 

Geometric mean 
AUC values at cycle 7 
µg.day/mL 

MabThera 
subcutaneous 
formulation 

134.6  3778  

MabThera 
intravenous 
formulation 

83.1  2734  

 
In a population pharmacokinetic analysis in 403 follicular lymphoma patients who received 
subcutaneous and/or intravenous MabThera, single or multiple infusions of MabThera as a single 
agent or in combination with chemotherapy, the population estimates of nonspecific clearance (CL1), 
initial specific clearance (CL2) likely contributed by B cells or tumour burden, and central 
compartment volume of distribution (V1) were 0.194 L/day, 0.535 L/day, and 4.37 L/day, respectively. 
The estimated median terminal elimination half-life of MabThera subcutaneous formulation was 
29.7 days (range, 9.9 to 91.2 days).The analysis data set contained 6003 quantifiable samples from 403 
patients administered SC and/or IV rituximab in trials BP22333 (3736 samples from 277 patients) and 
BO22334 (2267 samples from126 patients). Twenty nine (0.48%) post-dose observations (all from 
trial BP22333) were below the quantification limit. There were no missing covariate values except 
baseline B-cell count. Baseline tumour load was available only in trial BO22334. 
 



81 

Special populations 
 
In clinical trial BO22334, an effect was observed between body size and exposure ratios reported in 
cycle 7, between rituximab subcutaneous formulation 1400 mg q3w and rituximab intravenous 
formulation 375 mg/m2 q3w with Ctrough ratios of 2.29, 1.31, and 1.41 in patients with low, medium 
and high BSA, respectively (low BSA ≤ 1.70 m2; 1.70 m2 < medium BSA < 1.90 m2; high BSA 
≥ 1.90 m2). The corresponding AUCτ ratios were 1.66, 1.17 and 1.32. 
 
There was no evidence of clinically relevant dependencies of rituximab pharmacokinetics on age and 
sex. 
 
Anti-rituximab antibodies were detected in only 13 patients and did not result in any clinically relevant 
increase in steady-state clearance. 
 
5.3 Preclinical safety data 
 
Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in 
cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of 
B cells in peripheral blood and in lymphoid tissue.  
 
Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to 
100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus 
due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid 
organs of the foetuses was observed, which persisted post natally and was accompanied by a decrease 
in IgG level in the newborn animals affected. B cell counts returned to normal in these animals within 
6 months of birth and did not compromise the reaction to immunization. 
 
Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant 
for this molecule. No long-term animal studies have been performed to establish the carcinogenic 
potential of rituximab.  
Specific studies to determine the effects of rituximab or rHuPH20 on fertility have not been 
performed. In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive 
organs in males or females were observed. Additionally, no effects on semen quality were shown for 
rHuPH20. 
 
In embryofetal developmental studies in mice, rHuPH20 caused reduced fetal weight and loss of 
implantations at systemic exposures sufficiently in excess of human therapeutic exposure. 
There is no evidence of dysmorphogenesis (i.e. teratogenesis) resulting from systemic exposure to 
rHuPH20. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Recombinant human hyaluronidase (rHuPH20) 
L-histidine 
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate 
L-methionine 
Polysorbate 80 (E433) 
Water for injections  
 



82 

6.2 Incompatibilities 
 
No incompatibilities between MabThera subcutaneous formulation and polypropylene or 
polycarbonate syringe material or stainless steel transfer and injection needles and polyethylene Luer 
cone stoppers have been observed. 
 
6.3 Shelf life 
 
Unopened vial 
30 months 
 
After first opening 
Once transferred from the vial into the syringe, the solution of MabThera subcutaneous formulation is 
physically and chemically stable for 48 hours at 2 °C - 8 °C and subsequently for 8 hours at 30°C in 
diffuse daylight. 
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, preparation should take place in controlled and validated aseptic conditions. In-use 
storage times and conditions prior to use are the responsibility of the user. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from 
light. 
For storage conditions after first opening see section 6.3. 
 
6.5 Nature and contents of container 
 
Colourless type I glass vial with butyl rubber stopper with aluminium over seal and a pink plastic 
flip-off disk, containing 1400 mg/11.7 mL of rituximab. 
 
Each carton contains one vial. 
 
6.6 Special precautions for disposal and other handling 
 
MabThera is provided in sterile, preservative-free, non-pyrogenic, single use vials. A peel--off sticker 
is included on the vials which specifies the strength, route of administration and indication. This 
sticker should be removed from the vial and stuck onto the syringe prior to  use. The following points 
should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps:  
• Needles and syringes should never be reused 
• Place all used needles and syringes into a sharps container (puncture-proof disposable 

container).  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 



83 

8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/067/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 2 June 1998 
Date of latest renewal: 2 June 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

  

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


84 

1. NAME OF THE MEDICINAL PRODUCT 
 
MabThera 1600 mg solution for subcutaneous injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL contains 120 mg of rituximab. 
 
Each vial contains 1600 mg/ 13.4 mL rituximab. 
 
Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a 
glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and 
heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster 
ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including 
specific viral inactivation and removal procedures. 
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. 
 
Clear to opalescent, colourless to yellowish liquid with pH of 5.2 – 5.8 and osmolality of 300 - 400 
mOsmol/kg.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
MabThera is indicated in adults in combination with chemotherapy for the treatment of patients with 
previously untreated and relapsed/refractory chronic lymphocytic leukaemia (CLL). Only limited data 
are available on efficacy and safety for patients previously treated with monoclonal antibodies 
including MabThera or patients refractory to previous MabThera plus chemotherapy. 
 
See section 5.1 for further information.  
 
4.2 Posology and method of administration 
 
MabThera should be administered under the close supervision of an experienced healthcare 
professional, and in an environment where full resuscitation facilities are immediately available (see 
section 4.4).  
 
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and 
diphenhydramine, should always be given before each administration of MabThera. 
 
Premedication with glucocorticoids should be considered if MabThera is not given in combination 
with glucocorticoid-containing chemotherapy-.  
 
Posology 
 
The recommended dose of MabThera subcutaneous formulation used for adult patients is a 
subcutaneous injection at a fixed dose of 1600 mg irrespective of the patient’s body surface area.  
 



85 

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full 
dose of MabThera by intravenous infusion, using MabThera intravenous formulation (see section 4.4). 
 
If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, 
they should continue the subsequent cycles with MabThera intravenous formulation until a full 
intravenous dose is successfully administered.  
Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or 
subsequent cycles of treatment. 
 
It is important to check the medicinal product labels to ensure that the appropriate formulation 
(intravenous or subcutaneous formulation) and strength is being given to the patient, as prescribed. 
 
MabThera subcutaneous formulation is not intended for intravenous administration and should be 
given via subcutaneous injection only.   The 1600 mg strength is intended for subcutaneous use in 
CLL only. 
 
Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start 
of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL 
patients whose lymphocyte counts are > 25 x 109/L it is recommended to administer 
prednisone/prednisolone 100 mg intravenous shortly before administration with MabThera to decrease 
the rate and severity of acute infusion reactions and/or cytokine release syndrome. 
 
The recommended dosage of MabThera in combination with chemotherapy for previously untreated 
and relapsed/refractory patients is: MabThera intravenous formulation 375 mg/m2 body surface area 
administered on day 0 of the first cycle of treatment followed by MabThera subcutaneous formulation 
injected at a fixed dose of 1600 mg per cycle, on day 1 of each subsequent cycle (in total: 6 cycles).  
The chemotherapy should be given after MabThera administration. 
 
Dose adjustments during treatment 
 
No dose reductions of MabThera are recommended. When MabThera is given in combination with 
chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be 
applied (see section 4.8). 
 
Special populations 
 
Paediatric population 
The safety and efficacy of MabThera in children below 18 years has not been established. No data are 
available. 
 
Elderly 
No dose adjustment is required in elderly patients (aged >65 years).  
 
Method of administration 
 
Subcutaneous injections 
MabThera 1600 mg subcutaneous formulation should be administered as subcutaneous injection only, 
over approximately 7 minutes. The hypodermic injection needle must only be attached to the syringe 
immediately prior to administration to avoid potential needle clogging. 
 
MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall and 
never into areas where the skin is red, bruised, tender, hard or areas where there are moles or scars. 
 
No data are available on performing the injection in other sites of the body, therefore injections should 
be restricted to the abdominal wall. 
 



86 

During the treatment course with MabThera subcutaneous formulation, other medicinal products for 
subcutaneous administration should preferably be given at different sites. 
 
If an injection is interrupted it can be resumed at the same site or another location may be used, if 
appropriate. 
 
Intravenous infusion administration  
The Summary of Product Characteristics (SmPC) of MabThera 100 mg and 500 mg concentrate for 
solution for infusion should be referred to for information on dosing instructions and method of 
administration. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to murine proteins, hyaluronidase or to any of the other 
excipients listed in section 6.1.  
 
Active, severe infections (see section 4.4). 
 
Patients in a severely immunocompromised state. 
 
4.4 Special warnings and precautions for use 
 
Treacibility 
 
In order to improve traceability of biological medicinal products, the tradename and batch number of 
the administered product should be clearly recorded. 
 
The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation 
in the approved indications Treatment of non-Hodgkin’s lymphoma (strength 1400 mg) and Treatment 
of CLL (strength 1600 mg). For information related to the other indications, please refer to the SmPC 
of MabThera intravenous formulation.  
 
Progressive multifocal leukoencephalopathy 
 
Use of MabThera may be associated with an increased risk of progressive multifocal 
leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening 
neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing 
must be suspended until PML has been excluded. The clinician should evaluate the patient to 
determine if the symptoms are indicative of neurological dysfunction, and if so, whether these 
symptoms are possibly suggestive of PML. Consultation with a neurologist should be considered as 
clinically indicated. 
 
If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal 
fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.  
 
The physician should be particularly alert to symptoms suggestive of PML that the patient may not 
notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to 
inform their partner or caregivers about their treatment, since they may notice symptoms that the 
patient is not aware of. 
 
If a patient develops PML, the dosing of MabThera must be permanently discontinued.  
 
Following reconstitution of the immune system in immunocompromised patients with PML, 
stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and 
suspension of MabThera therapy may lead to similar stabilisation or improved outcome. 
 



87 

Infusion/Administration-related reactions 
 
MabThera is associated with infusion/administration-related reactions, which may be related to release 
of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically 
indistinguishable from acute hypersensitivity reactions. 
 
This set of reactions which includes syndrome of cytokine release, tumor lysis syndrome and 
anaphylactic and hypersensitivity reactions are described below. They are not specifically related to 
the route of administration of MabThera and can be observed with both formulations. 
 
Severe infusion-related reactions with fatal outcome have been reported during post-marketing use of 
the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after 
starting the first MabThera intravenous infusion. They were characterized by pulmonary events and in 
some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, 
chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8). 
 
Severe cytokine release syndrome is characterised by severe dyspnea, often accompanied by 
bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This 
syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, 
hyperkalaemia, hypocalcaemia, hyperphosphaetemia, acute renal failure, elevated lactate 
dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute 
respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, 
visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating 
the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour 
infiltration may be at greater risk of poor outcome and should be treated with increased caution. 
Patients who develop severe cytokine release syndrome should have their infusion interrupted 
immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial 
improvement of clinical symptoms may be followed by deterioration, these patients should be closely 
monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. 
Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in 
repeated severe cytokine release syndrome.  
 
Patients with a high tumour burden or with a high number (≥25 x 109/L) of circulating malignant cells, 
such as patients with CLL who may be at higher risk of especially severe cytokine release syndrome, 
should be treated with extreme caution. These patients should be very closely monitored throughout 
the first infusion. Consideration should be given to the use of a reduced infusion rate for the first 
infusion in these patients or a split dosing over two days during the first cycle and any subsequent 
cycles if the lymphocyte count is still >25 x 109/L. 
 
Anaphylactic and other hypersensitivity reactions have been reported following the intravenous 
administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity 
reactions typically occur within minutes after starting infusion. 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 allergic reaction during administration of MabThera. 
Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine 
release syndrome (described above). Reactions attributed to hypersensitivity have been reported less 
frequently than those attributed to cytokine release. 
 
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary 
oedema and acute reversible thrombocytopenia. 
 
Since hypotension may occur during MabThera administration, consideration should be given to 
withholding anti-hypertensive medicines 12 hours prior to giving MabThera. 
 
Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with 
MabThera intravenous formulation (including cytokine release syndrome accompanied by 
hypotension and bronchospasm in 10 % of patients) see section 4.8. These symptoms are usually 



88 

reversible with interruption of MabThera infusion and administration of an anti-pyretic, an 
antihistaminic, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if 
required. Please see cytokine release syndrome above for severe reactions. 
 
Administration related reactions have been observed in up to 50% of patients treated with MabThera 
subcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the 
subcutaneous injection consisted primarily of erythema pruritus, rash and injections site reactions such 
as pain, swelling and redness and were generally of mild or moderate (grade 1 or 2) and transient 
nature (see section 4.8). 
 
Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical 
trials. Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see 
section 4.8). Some local cutaneous reactions occurred more than 24 hours after the MabThera 
subcutaneous administration. The majority of local cutaneous reactions seen following administration 
of MabThera subcutaneous formulation was mild or moderate and resolved without any specific 
treatment. 
 
Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full 
dose of MabThera by intravenous infusion, using MabThera intravenous formulation. The highest risk 
of experiencing an administration related reaction is generally observed at cycle one. Beginning the 
therapy with MabThera intravenous infusion would allow a better handling of the administration 
reactions by slowing or stopping the intravenous infusion.  
 
If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, 
they should continue the subsequent cycles with MabThera intravenous formulation until a full 
intravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneous 
formulation can only occur at the second or subsequent cycles of treatment. 
 
As with the intravenous formulation, MabThera subcutaneous formulation should be administered in 
an environment where full resuscitation facilities are immediately available and under the close 
supervision of an experienced healthcare professional. Premedication consisting of an 
analgesic/antipyretic and an antihistamine should always be administered before each dose of 
MabThera subcutaneous formulation. Premedication with glucocorticoids should also be considered. 
 
Patients should be observed for at least 15 minutes following MabThera subcutaneous 
administration. A longer period may be appropriate in patients with an increased risk of 
hypersensitivity reactions. 
 
Patients should be instructed to contact their treating physician immediately if symptoms that are 
suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinal 
product administration. 
 
Cardiac disorders 
 
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or 
myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a 
history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. 
 
Haematological toxicities 
 
Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when 
considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L as 
clinical experience in this population is limited. The MabThera intravenous formulation has been used 
in 21 patients who underwent autologous bone marrow transplantation and other risk groups with a 
presumable reduced bone marrow function without inducing myelotoxicity. 
 



89 

Regular full blood counts, including neutrophil and platelet counts, should be performed during 
MabThera therapy.  
 
Infections 
 
Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). 
MabThera 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 MabThera in patients with a history of 
recurring or chronic infections or with underlying conditions which may further predispose patients to 
serious infection (see section 4.8).  
 
Cases of hepatitis B reactivation have been reported in patients receiving the MabThera intravenous 
formulation including fulminant hepatitis with fatal outcome. The majority of these patients were also 
exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL 
patients suggests that MabThera 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 MabThera. At minimum this should include HBsAg-status and HBcAb-status.  These 
can be complemented with other appropriate markers as per local guidelines. Patients with active 
hepatitis B disease should not be treated with MabThera. Patients with positive hepatitis B serology 
(either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be 
monitored and managed following local medical standards to prevent hepatitis B reactivation.  
 
Very rare cases of PML have been reported during post-marketing use of the MabThera intravenous 
formulation in CLL (see section 4.8). The majority of patients had received rituximab in combination 
with chemotherapy or as part of a hematopoietic stem cell transplant.  
 
Immunisation 
 
The safety of immunisation with live viral vaccines, following MabThera therapy has not been studied 
for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients 
treated with MabThera may receive non-live vaccinations; however, with non-live vaccines response 
rates may be reduced. In a non-randomized study, patients with relapsed low-grade NHL who received 
the MabThera intravenous formulation as monotherapy when compared to healthy untreated controls 
had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole 
Limpet Haemocyanin (KLH) neoantigen (4% vs. 69% when assessed for >2-fold increase in antibody 
titer). For CLL patients similar results are assumable considering similarities between both diseases, 
but this has not been investigated in clinical trials. 
 
Mean pre-therapeutic antibody titers against a panel of antigens (Streptococcus pneumoniae, influenza 
A, mumps, rubella and varicella) were maintained for at least 6 months after treatment with 
MabThera.  
 
Skin reactions 
 
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). In case of such an event, 
with suspected relationship to MabThera, treatment should be permanently discontinued. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Currently, there are limited data on possible drug interactions with MabThera.  
 
In CLL patients, co-administration with MabThera did not appear to have an effect on the 
pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of 
fludarabine and cyclophosphamide on the pharmacokinetics of MabThera. 



90 

 
Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have 
allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal 
antibodies. 
 
4.6 Fertility, pregnancy and lactation 
 
Contraception in males and females 
 
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing 
potential must employ effective contraceptive methods during and for 12 months after treatment with 
MabThera. 
 
Pregnancy 
 
IgG immunoglobulins are known to cross the placental barrier. 
 
B-cell levels in human neonates following maternal exposure to MabThera have not been studied in 
clinical 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 to 
mothers exposed to MabThera during pregnancy. Similar effects have been observed in animal studies 
(see section 5.3).For these reasons MabThera should not be administered to pregnant women unless 
the possible benefit outweighs the potential risk. 
 
Breast-feeding 
 
Whether rituximab is excreted in human milk is not known. However, because maternal IgG is 
excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should 
not breastfeed while treated with MabThera and for 12 months following MabThera treatment. 
 
Fertility 
 
Animal studies did not reveal deleterious effects of rituximab or recombinant human hyaluronidase 
(rHuPH20) on reproductive organs. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects of MabThera on the ability to drive and use machines have been performed, 
although the pharmacological activity and adverse reactions reported to date suggest that MabThera 
would have no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
The information provided in this section pertains to the use of MabThera in oncology.  
For information related to the autoimmune indications, please refer to the SmPC of MabThera 
intravenous formulation. 
 
Summary of the safety profile  
 
During the development programme, the safety profile of MabThera subcutaneous formulation was 
comparable to that of the intravenous formulation with the exception of local cutaneous reactions.  
Local cutaneous reactions including injection site reactions were very common in patients receiving 
MabThera subcutaneous formulation. In the NHL phase 3 trial SABRINA (BO22334), local cutaneous 
reactions were reported in up to 20% of patients receiving subcutaneous MabThera.  The most 
common local cutaneous reactions in the MabThera subcutaneous arm were injection site erythema 
(13%), injection site pain (7%), and injection site oedema (4%). Events seen following subcutaneous 
administration were mild or moderate, apart from one patient who reported a local cutaneous reaction 



91 

of Grade 3 intensity (injection site rash) following the first MabThera subcutaneous administration 
(Cycle 2).  Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most 
common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence 
decreased with subsequent injections. Similar events were observed in the CLL SAWYER trial 
(BO25341) and were reported in up to 42% of patients in the MabThera subcutaneous arm. Most 
common local cutaneous reactions were injection site erythema (26%), injection site pain (16%), and 
injection site swelling (5%).  Two patients in SAWYER trial who experienced Grade 3 local 
cutaneous reactions (injection site erythema, injection site pain and injection site swelling).  
 
Adverse reactions reported in MabThera subcutaneous formulation usage 
 
The risk of acute administration-related reactions associated with the subcutaneous formulation of 
MabThera was assessed in -three clinical trials: SparkThera and SABRINA (the two trials in NHL) 
and SAWYER the CLL trial.  
In trial SABRINA, severe administration-related reactions (grade≥3) were reported in two patients  
(2%) following administration of MabThera subcutaneous formulation .  These events were Grade 3 
injection site rash and dry mouth.  
In trial SparkThera, no severe administration-related reactions were reported. 
In SAWYER (BO25341), severe administration-related reactions (Grade ≥3) were reported in four 
patients (5%) following MabThera subcutaneous administration. These events were Grade 4 
thrombocytopenia and Grade 3 anxiety, injection-site erythema and urticaria. 
 
Adverse reactions reported in MabThera intravenous formulation usage 
 
Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia 
 
The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data from 
patients from clinical trials and from post-marketing surveillance. These patients were treated either 
with MabThera monotherapy (as induction treatment or maintenance treatment following induction 
treatment) or in combination with chemotherapy.  
 
The most frequently observed adverse reactions (ADRs) in patients receiving MabThera were 
infusion-related reactions which occurred in the majority of patients during the first infusion. The 
incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less 
than 1 % after eight doses of MabThera. 
  
Infectious events (predominantly bacterial and viral) occurred in approximately 30-55 % of patients 
during clinical trials in patients with NHL and in 30-50 % of patients during clinical trial in patients 
with CLL. 
 
The most frequent reported or observed serious adverse reactions were: 
• Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), see 

section 4.4. 
• Infections, see section 4.4. 
• Cardiovascular disorders, see section 4.4. 
 
Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.). 
 
The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are 
summarised in Table 1. Frequencies are defined as very common (≥ 1/10), common  (≥ 1/100 to 
< 1/10), uncommon  (≥  1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) and 
not known (cannot be estimated from the available data). Within each frequency grouping, undesirable 
effects are presented in order of decreasing seriousness. 
 
The ADRs identified only during post-marketing surveillance, and for which a frequency could not be 
estimated, are listed under “not known”. 
 



92 

Tabulated list of adverse reactions 
 
Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients 

with NHL and CLL disease treated with MabThera monotherapy/maintenance or in 
combination with chemotherapy  

MedDRA 
System Organ 

Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

Infections and 
infestations 

bacterial 
infections, 
viral 
infections, 
+bronchitis  
 

sepsis, 
+pneumonia, 
+febrile 
infection, 
+herpes zoster, 
+respiratory tract 
infection, fungal 
infections, 
infections of 
unknown 
aetiology, +acute 
bronchitis, 
+sinusitis, 
hepatitis B1  

 serious viral 
infection2 

  

Blood and 
lymphatic 
system 
disorders 

neutropenia, 
leucopenia, 
+febrile 
neutropenia, 
+thrombocyt
openia 
 

anaemia,  
+pancytopenia, 
+granulocytopeni
a 

coagulation 
disorders, 
aplastic 
anaemia, 
haemolytic 
anaemia, 
lymphadenop
athy 

 transient 
increase in 
serum IgM 
levels3 

late neutropenia3 

Immune 
system 
disorders 

infusion 
related 
reactions4, 
angioedema 

hypersensitivity  anaphylaxis tumour lysis 
syndrome, 
cytokine 
release 
syndrome4, 
serum 
sickness 

infusion-related 
acute reversible 
thrombocytopeni
a 4 

Metabolism 
and nutrition 
disorders 

 hyperglycaemia, 
weight decrease, 
peripheral 
oedema, face 
oedema, 
increased LDH, 
hypocalcaemia 

    

Psychiatric 
disorders 

  depression, 
nervousness, 

   

Nervous 
system 
disorders 

 paraesthesia, 
hypoaesthesia, 
agitation, 
insomnia, 
vasodilatation, 
dizziness, 
anxiety 

dysgeusia  peripheral 
neuropathy, 
facial nerve 
palsy5 

cranial 
neuropathy, 
loss of other 
senses5 

Eye disorders  lacrimation 
disorder, 
conjunctivitis 

  severe vision 
loss5 

 

Ear and 
labyrinth 
disorders 

 tinnitus, ear pain    hearing loss5 



93 

MedDRA 
System Organ 

Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

Cardiac 
disorders 

 +myocardial 
infarction4 and 6, 
arrhythmia, 
+atrial 
fibrillation, 
tachycardia, 
+cardiac disorder 

+left 
ventricular 
failure, 
+supraventric
ular 
tachycardia,  
+ventricular 
tachycardia,  
+angina,  
+myocardial 
ischaemia, 
bradycardia 

severe cardiac 
disorders 4 and 
6 

heart failure4 
and 6 

 

Vascular 
disorders 

 hypertension, 
orthostatic 
hypotension, 
hypotension  

  vasculitis 
(predominatel
y cutaneous), 
leukocytoclas
tic vasculitis 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Bronchospasm4, 
respiratory 
disease, chest 
pain, dyspnoea, 
increased cough, 
rhinitis 

asthma, 
bronchiolitis 
obliterans, 
lung disorder, 
hypoxia 

interstitial 
lung disease7 

respiratory 
failure4, 
 

lung infiltration,  

Gastrointestin
al disorders 

nausea  vomiting , 
diarrhoea, 
abdominal pain, 
dysphagia, 
stomatitis, 
constipation, 
dyspepsia, 
anorexia, throat 
irritation 

abdominal 
enlargement 

 gastro-intestin
al 
perforation7 

 

Skin and 
subcutaneous 
tissue 
disorders 

pruritis, 
rash, 
+alopecia  

urticaria, 
sweating, night 
sweats, +skin 
disorder 

  severe 
bullous skin 
reactions, 
Stevens-Johns
on Syndrome, 
toxic 
epidermal 
necrolysis 
(Lyell’s 
Syndrome) 7 

 

Musculoskelet
al, connective 
tissue 
disorders 

 hypertonia, 
myalgia, 
arthralgia, back 
pain, neck pain, 
pain 

    

Renal and 
urinary 
disorders 

    renal failure4  

General 
disorders and 
administratio
n site 
conditions 

fever , chills, 
asthenia, 
headache  

tumour pain, 
flushing, 
malaise, cold 
syndrome, 
+fatigue, 
+shivering,  
+multi-organ 
failure4 

infusion site 
pain 

   



94 

MedDRA 
System Organ 

Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

Investigations decreased 
IgG levels 

     

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with 
"+" where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria) reactions.  Only the 
highest frequency observed in the trials is reported 
1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 
2 see also section infection below  
3 see also section haematologic adverse reactions below 
4 see also section infusion-related reactions below. Rarely fatal cases reported 
5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera 

therapy 
6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with 

infusion-related reactions 
7 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 MabThera-arms compared to control arms: 
haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia. 
 
Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50 % of 
patients in clinical trials involving MabThera intravenous formulation, and were predominantly seen 
during the first infusion, usually in the first one to two hours. These symptoms mainly comprised 
fever, chills and rigors. Other symptoms 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-related reactions (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 cardiac 
conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, 
myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis 
syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or 
unknown frequencies. The incidence of infusion-related symptoms decreased substantially with 
subsequent intravenous infusions and is <1% of patients by the eighth cycle of MabThera (containing) 
treatment.  
 
Description of selected adverse reactions 
 
Infections  
MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreased 
serum immunoglobulins only in a minority of patients.  
 
Localized candida infections as well as Herpes zoster were reported at a higher incidence in the 
MabThera-containing arm of randomized studies. Severe infections were reported in about 4% of 
patients treated with MabThera monotherapy. Higher frequencies of infections overall, including 
grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when 
compared to observation. There was no cumulative toxicity in terms of infections reported over a 
2-year treatment period. In addition, other serious viral infections either new, reactivated or 
exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of 
patients had received MabThera in combination with chemotherapy or as part of a hematopoietic stem 
cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses 
(Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (PML) and hepatitis C 
virus. Cases of fatal PML that occurred after disease progression and retreatment have also been 
reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which 
were in patients receiving MabThera in combination with cytotoxic chemotherapy. In patients with 
relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary 
infection) was 2% in R-FC vs 0% in FC. Progression of Kaposi’s sarcoma has been observed in 



95 

MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in 
non-approved indications and the majority of patients were HIV positive. 
 
Haematologic adverse reactions  
In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities 
occurred 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 
MabThera maintenance treatment for up to 2 years, leucopoenia (5% vs. 2%, grade 3/4) and 
neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to 
observation. The incidence of thrombocytopenia was low (<1 %, grade 3/4) and was not different 
between treatment arms. During the treatment course in studies with MabThera in combination with 
chemotherapy, grade 3/4 leucopoenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), 
grade 3/4 neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 
19% in previously untreated CLL), grade 3/4 pancytopenia (R-FC 3% vs. FC 1% in previously 
untreated CLL)  were usually reported with higher frequencies when compared to chemotherapy 
alone. However, the higher incidence of neutropenia in patients treated with MabThera and 
chemotherapy was not associated with a higher incidence of infections and infestations compared to 
patients treated with chemotherapy alone. Studies with MabThera intravenous formulation in 
previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated 
with R-FC  neutropenia was prolonged (defined as neutrophil count remaining below 1x109/L between 
day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 
1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who 
recovered prior to day 42) following treatment with MabThera plus FC.There were no differences 
reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks 
after the last infusion of MabThera were reported. In the CLL first-line study, Binet stage C patients 
experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). 
In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of patients in 
the R-FC group compared to 9% of patients in the FC group.  
 
In studies of MabThera in patients with Waldenstrom’s macroglobulinaemia, transient increases in 
serum IgM levels have been observed following treatment initiation, which may be associated with 
hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline 
level within 4 months. 
 
Cardiovascular adverse reactions 
Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% of 
patients with the most frequently reported events being hypotension and hypertension. Cases of grade 
3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during 
infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders 
was comparable between patients treated with MabThera and observation. Cardiac events were 
reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular 
failure, myocardial ischemia) in 3% of patients treated with MabThera compared to <1% on 
observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of 
grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia 
and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the 
CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera 
infusion or were associated with predisposing conditions such as fever, infection, acute myocardial 
infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP 
and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart 
failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall 
incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and 
in the relapsed/refractory study (4% R-FC, 4% FC). 
 
Respiratory system 
Cases of interstitial lung disease, some with fatal outcome have been reported. 
 



96 

Neurologic disorders  
During the treatment period (induction treatment phase comprising of R-CHOP for at most eight 
cycles), four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced 
thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference 
between the treatment groups in the incidence of other thromboembolic events. In contrast, three 
patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the 
follow-up period.  In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low 
both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC). 
 
Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior 
leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual 
disturbance, headache, seizures and altered mental status, with or without associated hypertension. A 
diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognized 
risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, 
immunosuppressive therapy and/or chemotherapy. 
 
Gastrointestinal disorders 
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving 
MabThera for treatment of Non-Hodgkin’s lymphoma (NHL). In the majority of these cases, 
MabThera was administered with chemotherapy.  
 
IgG levels 
In the clinical trial evaluating MabThera maintenance treatment in relapsed/refractory follicular 
lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction 
treatment in both the observation and the MabThera groups. In the observation group, the median IgG 
level subsequently increased to above the LLN, but remained constant in the MabThera group. The 
proportion of patients with IgG levels below the LLN was about 60% in the MabThera group 
throughout the 2 year treatment period, while it decreased in the observation group (36% after 
2 years). 
 
Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell Syndrome) and Stevens-Johnson syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Patient subpopulations - MabThera monotherapy 
Elderly (≥ 65 years):  
The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared to 
younger patients (<65 years).  
 
Bulky disease: 
There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients 
without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in these 
two groups. 
 
Re-treatment: 
The percentage of patients reporting ADRs upon re-treatment with further courses of MabThera was 
similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 
ADRs). 
 
Patient subpopulations - MabThera combination therapy 
Elderly (≥ 65 years)  
The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients 
compared to younger patients (<65 years), with previously untreated or relapsed/refractory CLL. 
 



97 

Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Limited experience with doses higher than the approved dose of intravenous MabThera formulation is 
available from clinical trials in humans. The highest intravenous dose of MabThera tested in humans 
to date is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. No additional 
safety signals were identified. 
Patients who experience overdose should have immediate interruption of their infusion and be closely 
monitored. 
 
Three  patients in the MabThera subcutaneous NHL formulation trial SABRINA (BO22334) were 
inadvertently adminstered subcutaneous formulation  through the intravenous route up to a maximum 
rituximab dose of 2780 mg with no untoward effect.  
Patients who experience overdose or medication error with MabThera should be closely monitored. 
 
In the post-marketing setting five cases of MabThera overdose have been reported. Three cases had no 
reported adverse event. The two adverse events that were reported were flu-like symptoms, with a 
dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02 
 
MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an 
enzyme used to increase the dispersion and absorption of co-administered substances when 
administered subcutaneously. 
 
Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated 
phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95 % of all 
B cell non-Hodgkin’s lymphomas.  
 
CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, 
pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon 
antibody binding and is not shed from the cell surface. CD20 does not circulate in the plasma 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 can 
recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated 
cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and 
antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the 
surface of granulocytes, macrophages and NK cells. Rituximab binding to CD 20 antigen on B 
lymphocytes has also been demonstrated to induce cell death via apoptosis. 
 
Peripheral B cell counts declined below normal following completion of the first dose of MabThera. In 
patients treated for hematological malignancies, B cell recovery began within 6 months of treatment 
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 months post-induction 
therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


98 

observed following two infusions of 1000 mg MabThera separated by a 14 day interval. Peripheral 
blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the 
majority of patients by week 40, whether MabThera was administered as monotherapy or in 
combination with methotrexate. 
 
Clinical experience of MabThera subcutaneous formulation in chronic lymphocytic leukaemia 
 
A two-part phase Ib, multicenter, randomized, open-label, parallel-group trial (SAWYER BO25341) 
was conducted in patients with previously untreated CLL, to investigate the non-inferiority of the 
pharmacokinetic profile, together with efficacy and safety of MabThera subcutaneous formulation in 
combination with chemotherapy. 
 
The objective of the Part 1 was to select a MabThera subcutaneous formulation dose that resulted in 
comparable MabThera serum Ctrough levels compared with MabThera intravenous formulation. A total 
of 64 patients with CLL were enrolled at any point prior to cycle 5 during their treatment with 
MabThera intravenous formulation in combination with chemotherapy. The dose of 1600 mg of 
MabThera subcutaneous formulation was selected for the Part 2 of the study. 
 
The objective of the Part 2 was to establish the non-inferiority in observed Ctrough levels between the 
selected MabThera subcutaneous dose and the reference MabThera intravenous dose. 
A total of 176 patients with CLL were randomized into the following two treatment groups: 
 

• MabThera subcutaneous (n= 88); 1st cycle of MabThera intravenous 375 mg/m2 in 
combination with chemotherapy plus subsequent cycles (2-6) of MabThera subcutaneous 
1600mg in combination with chemotherapy. 

 
• MabThera intravenous (n= 88); 1st cycle of MabThera intravenous 375 mg/m2 in combination 

with chemotherapy followed by up to 5 cycles of MabThera intravenous 500 mg/m2 in 
combination with chemotherapy. 

The response rates for the analysis of 176 patients in SAWYER Part 2 are shown in Table 2. 
 
Table 2 Efficacy results for SAWYER (BO25341) (Intent to Treat Population) 

 Part 2 
N = 176 

Rituximab 
intravenous 
formulation 

(n = 88) 

Rituximab 
subcutaneous 
formulation 

(n = 88) 

ORRa 
Point estimate  80.7% (n = 71) 85.2% (n = 75) 

95% CI [70.9%, 88.3%] [76.1%, 91.9%] 

CRRa 
Point estimate  31.8% (n = 28) 27.3% (n = 24) 

95% CI [22.3%, 42.6%] [18.3%, 37.8%] 

PFSb 
Proportion with PFS event 42.0% (n = 37) 34.1% (n = 30) 

95% CI 0.76 [0.47%, 1.23%] 

ORR – Overall Response Rate 
CRR – Complete Response Rate 
PFS – Progression-Free Survival (proportion with event, disease progression/relapse or death from any cause) 
a – at 3 month follow-up visit (Part 2) 
b – at time of final analysis (median follow-up 53 months)  
 



99 

Overall the results confirm that MabThera subcutaneous formulation 1600 mg has a comparable 
benefit/risk profile to that of MabThera intravenous formulation 500 mg/m2. 
 
Immunogenicity 
Data from the development programme of MabThera subcutaneous formulation indicate that the 
formation of anti-rituximab antibodies after subcutaneous administration is comparable with that 
observed after intravenous administration. In SAWYER trial (BO25341) the incidence of 
treatment-induced/enhanced anti-rituximab antibodies was similar in the two treatment arms; 15% 
intravenous vs. 12% subcutaneous.  The incidence of treatment-induced/enhanced anti-rHuPH20 
antibodies, only measured in patients in the subcutaneous arm was 12%. None of the patients who 
tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies.  
 
The clinical relevance of the development of anti-rituximab or anti-rHuPH20 antibodies after 
treatment with MabThera subcutaneous formulation is not known. There was no impact of the 
presence of anti-rituximab or anti-rHuPH20 antibodies on safety, efficacy or PK of MabThera. 
 
Clinical experience of MabThera concentrate for solution for infusion in CLL 
 
In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients with 
relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, 
cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or MabThera in combination with 
FC (R-FC). MabThera was administered at a dosage of 375 mg/m2 during the first cycle one day prior 
to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients 
were excluded from the study in relapsed/refractory CLL if they had previously been treated with 
monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for 
at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 
FC) for the first-line study (Table 2a and Table 2b) and 552 patients (276 R-FC, 276 FC) for the 
relapsed/refractory study (Table 3) were analysed for efficacy. 
 
In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months 
in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overall 
survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p = 0.0319, 
log-rank test) (Table 2a). The benefit in terms of PFS was consistently observed in most patient 
subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 2b). 
 
Table 2a First--line treatment of chronic lymphocytic leukaemia 

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

Efficacy Parameter Kaplan-Meier Estimate of  
Median Time to Event (Months) 

Risk 
Reduction 

FC 
(N = 409) 

R-FC 
(N=408) 

Log-Rank  
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 
 



100 

Table 2b First-line treatment of chronic lymphocytic leukaemia 
Hazard ratios of progression-free survival according to Binet stage (ITT) – 48.1 
months median observation time 

Progression-free survival (PFS) 
 

Number of 
patients 

Hazard Ratio 
(95% CI) 

p-value (Wald 
test, not 

adjusted) FC R--FC 
Binet stage A 22 18 0.39 (0.15; 0.98) 0.0442 
Binet stage B 259 263 0.52 (0.41; 0.66) <0.0001 
Binet stage C 126 126 0.68 (0.49; 0.95) 0.0224 

CI: Confidence Interval 
 
In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6 
months in the R-FC group and 20.6 months in the FC group (p=0.0002, log--rank test). The benefit in 
terms of PFS was observed in almost all patient subgroups analysed according to disease risk at 
baseline. A slight but not significant improvement in overall survival was reported in the R-FC 
compared to the FC arm.  
No PK/clinical data are available in patients with a refractory or relapsing disease. 
 
Table 3 Treatment of relapsed/refractory chronic lymphocytic leukaemia -overview of 

efficacy results for MabThera plus FC vs. FC alone (25.3 months median 
observation time) 

Efficacy Parameter Kaplan--Meier Estimate of  
Median Time to Event (Months) 

Risk 
Reduction 

FC 
(N = 276) 

R--FC 
(N=276) 

Log--Rank  
p value 

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

Overall survival  51.9 NR 0.2874 17% 
     

Event free survival 19.3 28.7 0.0002 36% 

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

CR rates 13.0% 24.3% 0.0007  n.a. 

 Duration of response * 27.6 39.6 0.0252 31% 
Disease free survival (DFS)** 42.2 39.6 0.8842 --6% 
Time to new CLL treatment 34.2 NR 0.0024 35% 

Response rate and CR rates analysed using Chi--squared Test. 
*: only applicable to patients achieving a CR, nPR, PR;          NR: not reached                  n.a. not applicable  
**: only applicable to patients achieving a CR;      
 
Results from other supportive studies using MabThera in combination with other chemotherapy 
regimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment of 
previously untreated and/or relapsed/refractory CLL patients have also demonstrated high overall 
response rates with benefit in terms of PFS rates, albeit with modestly higher toxicity (especially 
myelotoxicity). These studies support the use of MabThera with any chemotherapy. 
Data in approximately 180 patients pre--treated with MabThera have demonstrated clinical benefit 
(including CR) and are supportive for MabThera re--treatment. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
rituximab in all subsets of the paediatric population with CLL. See Section 4.2 for information on 
paediatric use. 



101 

 
5.2 Pharmacokinetic properties 
 
Absorption 
 
MabThera at a fixed dose of 1600 mg was administered for 5 cycles subcutaneously at 4-weekly 
intervals, following the first cycle of MabThera intravenous formulation, in previously untreated CLL 
patients in combination with chemotherapy (fludarabine and cyclophosphamide (FC). The serum 
MabThera Cmax at Cycle 6 was lower in the subcutaneous arm than the intravenous, with geometric 
mean (CV%) values of 202 (36.1) μg/mL and 280 (24.6) μg/mL with the resulting geometric mean 
ratio (Cmax, SC/Cmax, IV) of 0.719 (90% CI: 0.653, 0.792).  The geometric mean tmax in the MabThera 
subcutaneous group was approximately 3 days as compared to the tmax occuring at or close to the end 
of the infusion for the MabThera intravenous group. The geometric mean Ctrough (CV%) values at 
Cycle 5 (pre-dose Cycle 6) were higher among the MabThera subcutaneous group than the MabThera 
intravenous group; 97.5 µg/mL (42.6) versus 61.5 µg/mL (63.9) respectively with a resulting adjusted 
geometric mean ratio [90% CI] of 1.53 [1.27-1.85]. Similarly, the geometric mean AUC (CV%) 
values at Cycle 6 were higher among the subcutaneous group than the intravenous group; 4088 
µg•day/mL (34.2) versus 3630 µg•day/mL (32.8) respectively) with a resulting adjusted geometric 
mean ratio [90% CI] of 1.10 [0.98-1.24]. 
Based on popPK analysis of study BO25341 (SAWYER) an absolute bioavailability of 68.4% was 
estimated. 
 
Distribution/Elimination 
 
The estimated half-life of Mabthera subcutaneous formulation of 1600 mg is 30 days, the estimated 
clearance is 0.22 L/day and the volume of distribution of the central compartment is 4.65 L. 
 
Special populations 
 
As typical for monoclonal antibodies, rituximab PK parameters depended on body size measures.  All 
clearance and volume parameters increased with BSA.  In addition, central volume was slightly (9%) 
lower in females compared to males.  Absorption parameters of subcutaneous  formulation, decreased 
with increasing BMI.  Conditional simulations that summarized the impact of all body size 
dependencies on rituximab exposure demonstrated that, while fixed subcutaneous dosing leads to 
larger differences in exposure (Ctrough and AUCτ) between subjects with low and high body sizes 
compared to body-weight-adjusted intravenous dosing, it allows to maintain Ctrough and AUCτ values 
for all body-size groups at the levels not lower than levels attained by intravenous dosing, thus 
achieving at least the same target saturation as for intravenousdosing.  For subjects weighing  > 90 kg, 
Ctrough values were the same for the intravenous and subcutaneous regimens.  For subjects weighing 
60-90 kg and  < 60 kg, average Ctrough values following intravenous dosing were approximately 16% 
and 34% lower compared to the subcutaneous regimen, respectively.  Similarly, for subjects in the 
high BSA tritile, Ctrough values were the same for the intravenous and subcutaneous regimens.  For 
subjects in the middle and low BSA tritiles, average Ctrough values following intravenous dosing were 
approximately 12% and 26% lower compared to the subcutaneous regimen. 
 
In addition to dependence on body size, time-dependent clearance was higher in subjects with higher 
baseline tumour size, which is consistent with target-mediated elimination.  Higher time-dependenet 
clearance in subjects with higher disease burden would lead to lower initial exposure and longer time 
needed to achieve the same exposure as in subjects with lower burden of the disease. 
 
5.3 Preclinical safety data 
 
Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in 
cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of 
B cells in peripheral blood and in lymphoid tissue.  
 



102 

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to 
100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus 
due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid 
organs of the foetuses was observed, which persisted post natally and was accompanied by a decrease 
in IgG level in the newborn animals affected. B cell counts returned to normal in these animals within 
6 months of birth and did not compromise the reaction to immunization. 
 
Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant 
for this molecule. No long-term animal studies have been performed to establish the carcinogenic 
potential of rituximab.  
Specific studies to determine the effects of rituximab or rHuPH20 on fertility have not been 
performed. In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive 
organs in males or females were observed. Additionally, no effects on semen quality were shown for 
rHuPH20. 
 
In embryofetal developmental studies in mice, rHuPH20 caused reduced fetal weight and loss of 
implantations at systemic exposures sufficiently in excess of human therapeutic exposure. 
There is no evidence of dysmorphogenesis (i.e. teratogenesis) resulting from systemic exposure to 
rHuPH20. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Recombinant human hyaluronidase (rHuPH20) 
L-histidine 
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate 
L-methionine 
Polysorbate 80 (E433) 
Water for injections  
 
6.2 Incompatibilities 
 
No incompatibilities between MabThera subcutaneous formulation and polypropylene or 
polycarbonate syringe material or stainless steel transfer and injection needles and polyethylene Luer 
cone stoppers have been observed. 
 
6.3 Shelf life 
 
Unopened vial 
30 months 
 
After first opening 
Once transferred from the vial into the syringe, the solution of MabThera subcutaneous formulation is 
physically and chemically stable for 48 hours at 2 °C - 8 °C and subsequently for 8 hours at 30°C in 
diffuse daylight. 
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, preparation should take place in controlled and validated aseptic conditions. In-use 
storage times and conditions prior to use are the responsibility of the user. 



103 

 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from 
light. 
For storage conditions after first opening see section 6.3. 
 
6.5 Nature and contents of container 
 
Colourless type I glass vial with butyl rubber stopper with aluminium over seal and a blue plastic 
flip-off disk, containing 1600 mg/13.4 mL of rituximab. 
 
Each carton contains one vial. 
 
6.6 Special precautions for disposal and other handling 
 
MabThera is provided in sterile, preservative-free, non-pyrogenic, single use vials. A peel--off sticker 
is included on the vials which specifies the strength, route of administration and indication. This 
sticker should be removed from the vial and stuck onto the syringe prior to use. The following points 
should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps:  
• Needles and syringes should never be reused 
• Place all used needles and syringes into a Sharps container (puncture-proof disposable 

container).  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/98/067/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 2 June 1998 
Date of latest renewal: 2 June 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 
  

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


104 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 
  



105 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Names and addresses of the manufacturers of the biological active substance 
 
Genentech Inc. 
1000 New Horizons Way 
Vacaville, CA 95688 
USA 
 
Genentech, Inc. 
1 Antibody Way 
Oceanside, CA 92056 5802 
USA 
 
Samsung BioLogics 
300, Songdo Bio Way (Daero) 
Yeonsu-gu, Incheon 21987,  
Korea  
 
Name and address of the manufacturer responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Str. 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the pharmacovigilance activities and 
interventions detailed in the agreed RMP presented in Module 1.8.2. of the Marketing Authorisation 
and any agreed and subsequent updates of the RMP. 
 



106 

An updated RMP should be submitted: 
• At the request of the European Medicines Agency. 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time.  
 
• Additional risk minimisation measures  
 
Non-oncology indications: 
 
The MAH must ensure that all physicians who are expected to prescribe MabThera are provided with 
the following: 
 
Product information 
Physician information 
Patient information 
Patient Alert card 
 
The Physician information about MabThera should contain the following key elements: 

• The need for close supervision during administration in an environment where full 
resuscitation facilities are immediately available 

• The need to check, prior to MabThera treatment, for infections, for immunosuppression, for 
prior/current medication affecting the immune system and recent history of, or planned, 
vaccination 

• The need to monitor patients for infections, especially PML, during and after MabThera 
treatment 

• Detailed information on the risk of PML, the need for timely diagnosis of PML and 
appropriate measures to diagnose PML 

• The need to advise patients on the risk of infections and PML, including the symptoms to be 
aware of and the need to contact their doctor immediately if they experience any. 

• The need to provide patients with the Patient Alert Card with each infusion 
 
The Patient information about MabThera should contain the following key elements: 

• Detailed information on the risk of infections and PML 
• Information on the signs and symptoms of infections, especially PML, and the need to 

contact their doctor immediately if they experience any 
• The importance of sharing this information with their partner or caregiver 
• Information on the Patient Alert Card 

 
The Patient Alert Card for MabThera in non-oncology indications should contain the following key 
elements: 

• The need to carry the card at all times and to show the card to all treating health care 
professionals 

• Warning on the risk of infections and PML, including the symptoms 
• The need for patients to contact their health care professional if symptoms occur 

 
The Physician information, Patient information and Patient Alert Card must be agreed with the 
National Competent Authorities prior to distribution. 

 



107 

Subcutaneous formulation: 
 
All healthcare professionals administering MabThera subcutaneous formulation will be provided with 
an Educational Material (« step by step guide » and « comparison card ») to minimise the risk of off 
label use and administration route error. 
 
  



108 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



109 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 

  



110 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
MabThera 100 mg concentrate for solution for infusion 
 
rituximab 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 10 mg/mL rituximab. 
 
 

3. LIST OF EXCIPIENTS 
 
Sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for 
injections.  
Read the leaflet for further information. 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
100 mg / 10 mL 
2 vials of 10 mL 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution 
Read the package leaflet before use 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 

8. EXPIRY DATE 
 
EXP  
 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Keep the container in the outer carton, in order to protect from light 
 
 



111 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/067/001 
 
 

13. BATCH NUMBER 
 
Batch 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER -- HUMAN READABLE DATA 
 
PC  
SN  
NN  
 
  



112 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 

 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
MabThera 100 mg concentrate for solution for infusion 
 
rituximab 
 
IV 
 
 

2. METHOD OF ADMINISTRATION 
 
For intravenous use after dilution 
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
Vial of 10 mL (10 mg/mL) 
100 mg / 10 mL 
 
 

6. OTHER 
 
  



113 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
MabThera 500 mg concentrate for solution for infusion 
 
rituximab 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 10 mg/mL rituximab. 
 
 

3. LIST OF EXCIPIENTS 
 
Sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for 
injections.  
Read the leaflet for further information.  
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
500 mg / 50 mL 
1 vial of 50 mL 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution 
Read the package leaflet before use 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 

8. EXPIRY DATE 
 
EXP  
 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Keep the container in the outer carton, in order to protect from light 
 
 



114 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/067/002 
 
 

13. BATCH NUMBER 
 
Batch 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER -- HUMAN READABLE DATA 
 
PC  
SN  
NN  
 
  



115 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 

 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
MabThera 500 mg concentrate for solution for infusion 
 
rituximab 
 
IV 
 
 

2. METHOD OF ADMINISTRATION 
 
For intravenous use after dilution 
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
Vial of 50 mL (10 mg/mL) 
500 mg / 50 mL 
 
 

6. OTHER 
 
  



116 

PATIENT ALERT CARD TEXT FOR NON-ONCOLOGY INDICATIONS 
MabThera Alert Card for patients with 

non-oncology diseases 

 

Why have I been given this card? 

This medicine may make you more 
likely to get infections. This card 
tells you: 

• What you need to know before 
having MabThera 

• What the signs of an infection are  

• What to do if you think you might 
be getting an infection. 

It also includes your name and 
doctor’s name and phone number on the 
back. 

What should I do with this card? 

• Keep this card with you all the 
time - such as in your wallet or 
purse. 

• Show this card to any doctor, 
nurse or dentist you see - not just 
the specialist who prescribes your 
MabThera. 

Keep this card with you for 2 years 
after your last dose of MabThera. 
This is because side effects can 
develop several months after you 
have had treatment. 

 

When should I not have MabThera? 

Do not have MabThera if you have an 
active infection or a serious problem with 
your immune system. 

Tell your doctor or nurse if you are taking 
or have previously taken medicines which 
may affect your immune system this 
includes chemo-therapy. 

 

What else do I need to know? 

Rarely MabThera can cause a serious brain 
infection, called “Progressive Multifocal 
Leukoencephalopathy” or PML. This can be 
fatal.  

• Signs of PML include:  
- Confusion, memory loss or 

problems thinking 
- Loss of balance or a change in the 

way you walk or talk 
- Decreased strength or weakness on 

one side of your body 
- Blurred vision or loss of vision. 

 
If you get any of these, tell a doctor or nurse 
straight away. You should also tell them 
about your MabThera treatment. 
 

Where can I get more information? 

See the MabThera package leaflet for more 
information. 

Treatment start date and contact details  

Date of most recent infusion: ____________ 
Date of first infusion: ___________________ 
Patient’s Name:________________________ 
Doctor’s Name:________________________ 
Doctor’s contact details:_________________ 
 
Make sure you have a list of all your 
medicines when you see a health care 
professional.  

Please talk to your doctor or nurse if you have 
any questions about the information in this 
card. 
 



117 

What are the signs of getting an infection? 

Look out for the following possible 
signs of infection: 
• Fever or cough all the time  
• Weight loss 
• Pain without injuring yourself 
• Feeling generally unwell or listless. 

If you get any of these, tell a doctor or 
nurse straight away. 

You should also tell them about your 
MabThera treatment. 

 
  



118 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
MabThera 1400 mg solution for subcutaneous injection 
 
rituximab 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 1400 mg/11.7 mL rituximab. 
 
 

3. LIST OF EXCIPIENTS 
 
Recombinant human hyaluronidase (rHuPH20) 
L-histidine 
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate 
L-methionine 
Polysorbate 80 
Water for injections  
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection  
1,400 mg/11.7 mL 
1 vial  
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use only  
 
Read the package leaflet before use. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 

8. EXPIRY DATE 
 
EXP  
 
 



119 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2 °C – 8 °C). Do not freeze.  
Keep the vial in the outer carton, in order to protect from light. 
 
 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/067/003 
 
 

13. BATCH NUMBER 
 
Batch 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER -- HUMAN READABLE DATA 
 
PC  
SN  
NN  
 
  



120 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 

 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
MabThera 1400 mg solution for subcutaneous injection 
 
rituximab 
 
subcutaneous 
 
 

2. METHOD OF ADMINISTRATION 
 
Only for subcutaneous use  
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1,400 mg/11.7 mL  
 
 

6. OTHER 
 
Information to appear on Peel-off sticker 
 
Lot 
MabThera 1400 mg  
rituximab 
 
1,400 mg/11.7 mL 
 
SC for Non-Hodgkin’s Lymphoma 
  



121 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
MabThera 1600 mg solution for subcutaneous injection 
 
rituximab 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 1600 mg/13.4 mL rituximab. 
 
 

3. LIST OF EXCIPIENTS 
 
Recombinant human hyaluronidase (rHuPH20) 
L-histidine 
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate 
L-methionine 
Polysorbate 80 
Water for injections  
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection  
1,600 mg/13.4 mL 
1 vial  
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use only  
 
Read the package leaflet before use. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 

8. EXPIRY DATE 
 
EXP  
 
 



122 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2 °C – 8 °C). Do not freeze.  
Keep the vial in the outer carton, in order to protect from light. 
 
 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/067/004 
 
 

13. BATCH NUMBER 
 
Batch 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER -- HUMAN READABLE DATA 
 
PC  
SN  
NN  
 
  



123 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 

 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
MabThera 1600 mg solution for subcutaneous injection 
 
rituximab 
 
subcutaneous 
 
 

2. METHOD OF ADMINISTRATION 
 
Only for subcutaneous use  
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1,600 mg/13.4 mL  
 
 

6. OTHER 
 

Information to appear on Peel-off sticker 
 
Lot 
MabThera 1600 mg  
rituximab 
 
1,600 mg/13.4 mL 
 
SC for Chronic Lymphocytic Leukaemia 
 
  



124 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



125 

Package leaflet: Information for the patient  
 

MabThera 100 mg concentrate for solution for infusion  
MabThera 500 mg concentrate for solution for infusion 

rituximab  
 
Read this leaflet carefully before you start taking this medicine because it contains important 
information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What MabThera is and what it is used for 
2. What you need to know before you use MabThera 
3. How to use MabThera 
4. Possible side effects 
5. How to store MabThera 
6. Contents of the pack and other information 
 
 
1. What MabThera is and what it is used for 
 
What MabThera is 
MabThera contains the active substance “rituximab”. This is a type of protein called a “monoclonal 
antibody”. It sticks to the surface of a type of white blood cell called “B-Lymphocyte”. When 
rituximab sticks to the surface of this cell, the cell dies. 
 
What MabThera is used for 
MabThera may be used for the treatment of several different conditions in adults and children. Your 
doctor may prescribe MabThera for the treatment of: 
 
a) Non-Hodgkin’s Lymphoma 
This is a disease of the lymph tissue (part of the immune system) that affects a type of white blood cell 
called B-Lymphocytes. 
In adults MabThera can be given alone or with other medicines called “chemotherapy”.  
In adult patients where the treatment is working, MabThera may be used as a maintenance treatment 
for 2 years after completing the initial treatment. 
In children and adolescents, MabThera is given in combination with “chemotherapy”. 
 
b) Chronic lymphocytic leukaemia 
Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL affects a 
particular lymphocyte, the B cell, which originates from the bone marrow and develops in the lymph 
nodes. Patients with CLL have too many abnormal lymphocytes, which accumulate mainly in the bone 
marrow and blood. The proliferation of these abnormal B-lymphocytes is the cause of symptoms you 
may have. MabThera in combination with chemotherapy destroys these cells which are gradually 
removed from the body by biological processes. 
 
c) Rheumatoid arthritis 
MabThera is used for the treatment of rheumatoid arthritis. Rheumatoid arthritis is a disease of the 
joints. B lymphocytes are involved in the cause of some of the symptoms you have. MabThera is used 
to treat rheumatoid arthritis in people who have already tried some other medicines which have either 
stopped working, have not worked well enough or have caused side effects. MabThera is usually taken 
together with another medicine called methotrexate.  
 



126 

MabThera slows down the damage to your joints caused by rheumatoid arthritis and improves your 
ability to do normal daily activities. 
 
The best responses to MabThera are seen in those who have a positive blood test to rheumatoid factor 
(RF) and/or anti-Cyclic Citrullinated Peptide (anti-CCP). Both tests are commonly positive in 
rheumatoid arthritis and aid in confirming the diagnosis. 
 
d) Granulomatosis with polyangiitis or microscopic polyangiitis 
MabThera is used for the treatment of adults and children 2 years of age and older with 
granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis) or microscopic 
polyangiitis, taken in combination with corticosteroids. 
 
Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the 
blood vessels which mainly affects the lungs and kidneys, but may affect other organs as well. B 
lymphocytes are involved in the cause of these conditions. 
 
e) Pemphigus vulgaris 
MabThera is used for the treatment of patients with moderate to severe pemphigus vulgaris. 
Pemphigus vulgaris is an autoimmune condition that causes painful blisters on the skin and lining of 
the mouth, nose, throat and genitals. 
 
 
2. What you need to know before you use MabThera 
 
Do not take MabThera if: 
• you are allergic to rituximab, other proteins which are like rituximab, or any of the other 

ingredients of this medicine (listed in section 6) 
• you have a severe active infection at the moment  
• you have a weak immune system. 
• you have severe heart failure or severe uncontrolled heart disease and have rheumatoid arthritis, 

granulomatosis with polyangiitis, microscopic polyangiitis or pemphigus vulgaris. 
 
Do not have MabThera if any of the above apply to you. If you are not sure, talk to your doctor, 
pharmacist or nurse before you are given MabThera. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before you are given MabThera if: 
 
• you have ever had or might now have a hepatitis infection. This is because in a few cases, 

MabThera could cause hepatitis B to become active again, which can be fatal in very rare cases. 
Patients who have ever had hepatitis B infection will be carefully checked by their doctor for 
signs of this infection 

• you have ever had heart problems (such as angina, palpitations or heart failure) or breathing 
problems.   

 
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
you are given MabThera. Your doctor may need to take special care of you during your treatment with 
MabThera. 
 
If you have rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis or 
pemphigus vulgaris also tell your doctor 
• if you think you may have an infection, even a mild one like a cold. The cells that are affected 

by MabThera help to fight infection and you should wait until the infection has passed before 
you are given MabThera. Also please tell your doctor if you had a lot of infections in the past or 
suffer from severe infections.  



127 

• if you think you may need any vaccinations in the near future, including vaccinations needed to 
travel to other countries. Some vaccines should not be given at the same time as MabThera or in 
the months after you receive MabThera. Your doctor will check if you should have any vaccines 
before you receive MabThera. 

 
Children and adolescents 
Non-Hodgkin’s lymphoma 
MabThera can be used for the the treatment of children and adolescents, 6 months of age and older, 
with non-Hodgkin’s lymphoma, specifically CD20 positive diffuse large B-cell lymphoma (DLBCL), 
Burkitt lymphoma (BL)/Burkitt leukaemia (mature B-cell acute leukaemia) (BAL) or Burkitt-like 
lymphoma (BLL). 
Talk to your doctor, pharmacist or nurse before you are given this medicine if you, or your child, are 
under 18 years of age.  
 
Granulomatosis with polyangiitis or microscopic polyangiitis 
MabThera can be used for treatment of children and adolescents, 2 years of age and older, with 
granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis) or microscopic 
polyangiitis. There is not much information about the use of MabThera in children and adolescents 
with other diseases. 
 
Talk to your doctor, pharmacist or nurse before you are given this medicine if you, or your child, are 
under 18 years of age. 
 
Other medicines and MabThera 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription and herbal medicines. This is 
because MabThera can affect the way some other medicines work. Also some other medicines can 
affect the way MabThera works.  
 
In particular, tell your doctor: 
• if you are taking medicines for high blood pressure. You may be asked not to take these other 

medicines 12 hours before you are given MabThera. This is because some people have a fall in 
their blood pressure while they are being given MabThera. 

• if you have ever taken medicines which affect your immune system – such as chemotherapy or 
immune-suppressive medicines. 

 
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
you are given MabThera. 
 
Pregnancy and breast-feeding  
You must tell your doctor or nurse if you are pregnant, think that you might be pregnant or are 
planning to become pregnant. This is because MabThera can cross the placenta and may affect your 
baby. 
If you can get pregnant, you and your partner must use an effective method of contraception while 
using MabThera. You must also do this for 12 months after your last treatment with MabThera. 
Do not breast-feed while you are being treated with MabThera. Also do not breast-feed for 12 months 
after your last treatment with MabThera. This is because MabThera may pass into breast milk. 
 
Driving and using machines 
It is not known whether MabThera has an effect on you being able to drive or use any tools or 
machines. 
 
MabThera contains sodium 
This medicine contains 52.6 mg sodium (main component of the cooking/table salt) in each 10 mL 
vial and 263.2 mg in each 50 mL vial.  
This is equivalent to 2.6% (for 10ml vial) and 13.2% (for 50ml vial) of the recommended maximum 
daily dietary intake of sodium for an adult. 



128 

 
 
3. How MabThera is given 
 
How it is given 
MabThera will be given to you by a doctor or nurse who is experienced in the use of this treatment. 
They will watch you closely while you are being given this medicine. This is in case you get any side 
effects.  
You will always be given MabThera as a drip (intra-venous infusion). 
 
Medicines given before each MabThera administration 
Before you are given MabThera, you will be given other medicines (pre-medication) to prevent or 
reduce possible side effects. 
 
How much and how often you will receive your treatment 
 
a) If you are being treated for non-Hodgkin’s Lymphoma 

• If you are having MabThera alone 
MabThera will be given to you once a week for 4 weeks. Repeated treatment courses with 
MabThera are possible. 

• If you are having MabThera with chemotherapy 
MabThera will be given to you on the same day as your chemotherapy. This is usually given 
every 3 weeks up to 8 times. 

• If you respond well to treatment, you may be given MabThera as a maintenance treatment 
every 2 or 3 months for two years. Your doctor may change this, depending on how you 
respond to the medicine. 

• If you are less than 18 years of age, you will be given MabThera with chemotherapy.  You 
will receive MabThera up to 6 times over a 3.5 – 5.5 month period. 

 
b) If you are being treated for chronic lymphocytic leukaemia 
When you are treated with MabThera in combination with chemotherapy, you will receive MabThera 
infusions on day 0 cycle 1 then day 1 of each cycle for 6 cycles in total. Each cycle has a duration of 
28 days. The chemotherapy should be given after the MabThera infusion. Your doctor will decide if 
you should receive concomitant supportive therapy. 
 
c) If you are being treated for rheumatoid arthritis 
Each course of treatment is made up of two separate infusions which are given 2 weeks apart. 
Repeated courses of treatment with MabThera are possible. Depending on the signs and symptoms of 
your disease, your doctor will decide when you should receive more MabThera. This may be months 
from now. 
 
d) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis 
Treatment with MabThera uses four separate infusions given at weekly intervals. Corticosteroids will 
usually be given by injection before the start of MabThera treatment. Corticosteroids given by mouth 
may be started at any time by your doctor to treat your condition. 
If you are 18 years of age and older and respond well to treatment, you may be given MabThera as a 
maintenance treatment.  This will be administered as 2 separate infusions which are given 2 weeks 
apart, followed by 1 infusion every 6 months for at least 2 years. Your doctor may decide to treat you 
longer with MabThera (up to 5 years), depending on how you respond to the medicine. 
 
e) If you are being treated for pemphigus vulgaris 
Each course of treatment is made up of two separate infusions which are given 2 weeks apart. If you 
respond well to treatment, you may be given MabThera as a maintenance treatment.  This will be 
administered 1 year and 18 months after the initial treatment and then every 6 months as needed or 
your doctor may change this, depending on how you respond to the medicine. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 



129 

 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Most side effects are mild to moderate but some may be serious and require treatment. Rarely, some of 
these reactions have been fatal. 
 
Infusion reactions 
During or within the first 24 hours of the infusion you may develop fever, chills and shivering. Less 
frequently, some patients may experience pain at the infusion site, blisters, itching, sickness (nausea), 
tiredness, headache, breathing difficulties, blood pressure raised, wheezing, throat discomfort, tongue 
or throat swelling, itchy or runny nose, vomiting, flushing or palpitations, heart attack or low number 
of platelets. If you have heart disease or angina, these reactions might get worse. Tell the person 
giving you the infusion immediately if you or your child develops any of these symptoms, as the 
infusion may need to be slowed down or stopped. You may require additional treatment such as an 
antihistamine or paracetamol. When these symptoms go away, or improve, the infusion can be 
continued. These reactions are less likely to happen after the second infusion. Your doctor may decide 
to stop your MabThera treatment if these reactions are serious. 
 
Infections 
Tell your doctor immediately if you or your child gets signs of an infection including: 
 
• fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell 
• memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare, 

serious brain infection, which has been fatal (Progressive Multifocal Leukoencephalopathy or 
PML). 

You might get infections more easily during your treatment with MabThera.  
These are often colds, but there have been cases of pneumonia or urinary infections. These are listed 
below under “Other side effects”. 
 
If you are being treated for rheumatoid arthritis, granulomatosis with polyangiitis, microscopic 
polyangiitis or pemphigus vulgaris, you will also find this information in the Patient Alert Card you 
have been given by your doctor.  It is important that you keep this Alert Card and show it to your 
partner or caregiver. 
 
Skin Reactions 
Very rarely, severe blistering skin conditions that can be life-threatening may occur.  Redness, often 
associated with blisters, may appear on the skin or on mucous membranes, such as inside the mouth, 
the genital areas or the eyelids, and fever may be present.  Tell your doctor immediately if you 
experience any of these symptoms. 
 
Other side effects include: 
a) If you or your child are being treated for non-Hodgkin’s Lymphoma or chronic 
lymphocytic leukaemia 
 

Very common side effects (may affect more than 1 in 10 people): 
• bacterial or viral infections, bronchitis 
• low number of white blood cells, with or without fever or blood cells called “platelets” 
• feeling sick (nausea) 
• bald spots on the scalp, chills, headache 
• lower immunity – because of lower levels of anti-bodies called “immunoglobulins” (IgG) in 

the blood which help protect against infection 
 



130 

Common side effects (may affect up to 1 in 10 people): 
• infections of the blood (sepsis), pneumonia, shingles, cold, bronchial tube infections, fungal 

infections, infections of unknown origin, sinus inflammation, hepatitis B 
• low number of red blood cells (anaemia), low number of all blood cells 
• allergic reactions (hypersensitivity) 
• high blood sugar level, weight loss, swelling in the face and body, high levels of the enzyme 

“LDH” in the blood, low calcium levels in the blood 
• unusual feelings of the skin – such as numbness, tingling, pricking, burning, a creeping skin 

feeling, reduced sense of touch  
• feeling restless, problems falling asleep 
• becoming very red in the face and other areas of the skin as a consequence of dilation of the 

blood vessels 
• feeling dizzy or anxious 
• producing more tears, tear duct problems, inflamed eye (conjunctivitis) 
• ringing sound in the ears, ear pain 
• heart problems – such as heart attack, uneven or fast heart rate 
• high or low blood pressure (low blood pressure especially when standing upright) 
• tightening of the muscles in the airways which causes wheezing (bronchospasm), 

inflammation, irritation in the lungs, throat or sinuses, being short of breath, runny nose 
• being sick (vomiting), diarrhoea, pain in the stomach, irritation or ulcers in the throat and 

mouth, problems swallowing, constipation, indigestion  
• eating disorders, not eating enough, leading to weight loss 
• hives, increased sweating, night sweats 
• muscle problems – such as tight muscles, joint or muscle pain, back and neck pain 
• tumour pain 
• general discomfort or feeling uneasy or tired, shaking, signs of flu 
• multiple-organ failure. 
 

Uncommon side effects (may affect up to 1 in 100 people): 
• blood clotting problems, decrease of red blood cell production and increase of red blood cell 

destruction (aplastic haemolytic anaemia), swollen or enlarged lymph nodes 
• low mood and loss of interest or enjoyment in doing things, feeling nervous 
• taste problems – such as changes in the way things taste 
• heart problems – such as reduced heart rate or chest pain (angina) 

asthma, too little oxygen reaching the body organs 
• swelling of the stomach. 
 

Very rare side effects (may affect up to 1 in 10, 000 people): 
• short term increase in the amount of some types of anti-bodies in the blood (called 

immunoglobulins – IgM), chemical disturbances in the blood caused by break-down of dying 
cancer cells 

• nerve damage in arms and legs, paralysed face 
• heart failure 
• inflammation of blood vessels including those leading to skin symptoms 
• respiratory failure 
• damage to the intestinal wall (perforation) 
• severe skin problems causing blisters that can be life-threatening. Redness, often associated 

with blisters, may appear on the skin or on mucous membranes, such as inside the mouth, the 
genital areas or the eyelids, and fever may be present. 

• kidney failure  
• severe vision loss  
 



131 

Not known (it is not known how often these side effects happen):  
• a reduction in white blood cells which does not happen straight away 
• reduced platelets number just after the infusion – this can be reversed, but can be fatal in rare 

cases 
• hearing loss, loss of other senses 
  

Children and adolescents with non-Hodgkin’s lymphoma: 
In general, side effects in children and adolescents with non-Hodgkin’s lymphoma were similar to 
those in adults with non-Hodgkin’s lymphoma or chronic lymphocytic leukaemia. The most common 
side effects seen were fever associated with low levels of a type of white blood cell (neutrophil), 
inflammation or sores in the lining of the mouth, and allergic reactions (hypersensitivity).  

 
b) If you are being treated for rheumatoid arthritis 

Very common side effects (may affect more than 1 in 10 people):  
• Infections such as pneumonia (bacterial)  
• Pain on passing water (urinary tract infection) 
• Allergic reactions that are most likely to occur during an infusion, but can occur up-to 

24-hours after infusion 
• Changes in blood pressure, nausea, rash, fever, feeling itchy, runny or blocked nose and 

sneezing, shaking, rapid heart beat, and tiredness 
• Headache 
• Changes in laboratory tests carried out by your doctor. These include a decrease in the amount 

of some specific proteins in the blood (immunoglobulins) which help protect against infection. 
 
Common side effects (may affect up to 1 in 10 people): 

• Infections such as bronchial tube inflammation (bronchitis) 
• A feeling of fullness or a throbbing pain behind the nose, cheeks and eyes (sinusitis), pain in 

the abdomen, vomiting  and diarrhoea, breathing problems 
• Fungal foot infection (athlete’s foot) 
• High cholesterol levels in the blood 
• Abnormal sensations of the skin, such as numbness, tingling, pricking or burning, sciatica, 

migraine, dizziness 
• Loss of hair 
• Anxiety, depression 
• Indigestion, diarrhoea, acid reflux, irritation and /or ulceration of the throat and the mouth 
• Pain in the tummy, back, muscles and/or joints 

 
Uncommon side effects (may affect up to 1 in 100 people): 

• Excess fluid retention in the face and body 
• Inflammation, irritation and / or tightness of the lungs, and throat, coughing 
• Skin reactions including hives, itching and rash 
• Allergic reactions including wheezing or shortness of breath, swelling of the face and tongue, 

collapse 
 
Very rare side effects (may affect up to 1 in 10, 000 people): 

• A complex of symptoms occurring within a few weeks of an infusion of MabThera including 
allergic like reactions such as rash, itching, joint pain, swollen lymph glands and fever 

• severe blistering skin conditions that can be life-threatening. Redness, often associated with 
blisters, may appear on the skin or on mucous membranes, such as inside the mouth, the 
genital areas or the eyelids, and fever may be present. 

 
Other rarely-reported side-effects due to MabThera include a decreased number of white cells in the 
blood (neutrophils) that help to fight against infection. Some infections may be severe (please see 
information on Infections within this section). 
 



132 

c) If you or your child are being treated for granulomatosis with polyangiitis or microscopic 
polyangiitis 
 
Very common side effects (may affect more than 1 in 10 people): 

• infections, such as chest infections, urinary tract infections (pain on passing water), colds and 
herpes infections 

• allergic reactions that are most likely to occur during an infusion, but can occur up-to 24-hours 
after infusion 

• diarrhoea 
• coughing or shortness of breath 
• nose bleeds 
• raised blood pressure 
• painful joints or back 
• muscle twitches or shakiness 
• feeling dizzy 
• tremors (shakiness, often in the hands) 
• difficulty sleeping (insomnia) 
• swelling of the hands or ankles  

 
Common side effects (may affect up to 1 in 10 people): 

• indigestion 
• constipation 
• skin rashes, including acne or spots 
• flushing or redness of the skin 
• fever 
• blocked or runny nose 
• tight or painful muscles 
• pain in the muscles or in the hands or feet 
• low number of red blood cells (anaemia) 
• low numbers of platelets in the blood 
• an increase in the amount of potassium in the blood 
• changes in the rhythm of the heart, or the heart beating faster than normal 
 

Very rare side effects (may affect up to 1 in 10, 000 people): 
• severe blistering skin conditions that can be life-threatening. Redness, often associated with 

blisters, may appear on the skin or on mucous membranes, such as inside the mouth, the genital 
areas or the eyelids, and fever may be present. 

• recurrence of a previous Hepatitis B infection 
 

Children and adolescents with granulomatosis with polyangiitis or microscopic polyangiitis 
In general, side effects in children and adolescents with granulomatosis with polyangiitis or 
microscopic polyangiitis were of a similar type to those in adults with granulomatosis with 
polyangiitis or microscopic polyangiitis. Most common side effects seen were infections, allergic 
reactions and feeling sick (nausea).  
 
d) If you are being treated for pemphigus vulgaris 
 
Very common side effects (may affect more than 1 in 10 people): 

• allergic reactions that are most likely to occur during an infusion, but can occur up to 24 hours 
after infusion 

• headache 
• infections such as chest infections 
• long lasting depression 
• loss of hair 

 



133 

Common side effects (may affect up to 1 in 10 people): 
• infections such as common cold, herpes infections, eye infection, oral thrush and urinary tract 

infections (pain on passing urine) 
• mood disorders such as irritability and depression 
• skin disorders such as itching, hives, and benign lumps 
• feeling tired or dizzy 
• fever 
• painful joints or back 
• pain in the tummy 
• pain in the muscles 
• heart beating faster than normal 

 
MabThera may also cause changes in laboratory tests carried out by your doctor.  
If you are having MabThera with other medicines, some of the side effects you may get may be due to 
the other medicines. 
 
Reporting of side effects 
If you get any side effects talk to your doctor, pharmacist or nurse. This includes any side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine 
 
 
5. How to store MabThera 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from 
light. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines that you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What MabThera contains 
 
• The active ingredient in MabThera is called rituximab.  
 The 10 mL vial contains 100 mg of rituximab (10 mg/mL).  
 The 50 mL vial contains 500 mg of rituximab (10 mg/mL). 
• The other ingredients are sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, 

hydrochloric acid and water for injections. 
 
What MabThera looks like and contents of the pack 
 
MabThera is a clear, colourless solution, supplied as a concentrate for solution for infusion.  
10 mL vial – Pack of 2 vials 
50 mL vial – Pack of 1 vial 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


134 

Marketing Authorisation Holder 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
 
Roche Pharma AG 
Emil-Barell-Str. 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark 
Roche a/s  
Tlf: +45 - 36 39 99 99 
 

Malta 
(See Ireland) 
  

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33  (0)1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: + 385 1 47 22 333 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 



135 

Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 

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


136 

 Package leaflet: Information for the patient  
 

MabThera 1400 mg solution for subcutaneous injection  
rituximab  

 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What MabThera is and what it is used for 
2. What you need to know before you are given MabThera  
3. How MabThera is given 
4. Possible side effects 
5. How to store MabThera  
6. Contents of the pack and other information 
 
 
1. What MabThera is and what it is used for 
 
What MabThera is 
MabThera contains the active substance “rituximab”. This is a type of protein called a “monoclonal 
antibody”. It sticks to the surface of a type of white blood cell called “B-Lymphocyte”. When 
rituximab sticks to the surface of this cell, the cell dies. 
MabThera is available as a medicine given as a drip (called MabThera 100 mg or MabThera 500 mg, 
concentrate for solution for infusion) and as a medicine for injection under your skin (called 
MabThera 1400 mg or MabThera 1600 mg, solution for subcutaneous injection). 
 
What MabThera is used for 
MabThera 1400 mg is used to treat Non-Hodgkin’s lymphoma in adults. 
• This is a disease of the lymph tissue (part of the immune system) that affects a type of white 

blood cell called B-Lymphocytes. 
 
MabThera 1400 mg can be given alone or with other medicines called “chemotherapy”.  
 
You will always be given MabThera as a drip (intra-venous infusion) at the start of your treatment.  
 
After this, you will be given MabThera as an injection under your skin. Your doctor will decide when 
to start MabThera injections. 
 
In patients where the treatment is working, MabThera may be used as a maintenance treatment for 2 
years after completing the initial treatment. 
 
 
2 What you need to know before you are given MabThera 
 
Do not have MabThera if: 
• you are allergic to rituximab, other proteins which are like rituximab, or any of the other 

ingredients of this medicine (listed in section 6) 
• you are allergic to hyaluronidase (an enzyme that helps to increase the absorption of injected 

 active substance)  
• you have a severe active infection at the moment 
• you have a weak immune system. 



137 

 
Do not have MabThera if any of the above apply to you. If you are not sure, talk to your doctor, 
pharmacist or nurse before you are given MabThera. 
  
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before you are given MabThera if: 
• you have ever had or might now have a hepatitis infection. This is because in a few cases, 

MabThera could cause hepatitis B to become active again, which can be fatal in very rare cases. 
Patients who have ever had hepatitis B infection will be carefully checked by their doctor for 
signs of this infection 

• you have ever had heart problems (such as angina, palpitations or heart failure) or breathing 
problems.  

 
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
you are given MabThera. Your doctor may need to take special care of you during your treatment with 
MabThera. 
 
Children and adolescents 
Talk to your doctor, pharmacist or nurse before you are given this medicine if you, or your child, are 
under 18 years of age. This is because there is not much information about the use of MabThera in 
children and adolescents. 
 
Other medicines and MabThera  
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription and herbal medicines. This is 
because MabThera can affect the way some other medicines work. Also some other medicines can 
affect the way MabThera works.  
 
In particular, tell your doctor: 
• if you are taking medicines for high blood pressure. You may be asked not to take these other 

medicines 12 hours before you are given MabThera. This is because some people have a fall in 
their blood pressure while they are being given MabThera 

• if you have ever taken medicines which affect your immune system – such as chemotherapy or 
immune-suppressive medicines. 

 
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
you are given MabThera. 
 
Pregnancy and breast-feeding  
You must tell your doctor or nurse if you are pregnant, think that you might be pregnant or are 
planning to become pregnant. This is because MabThera can cross the placenta and may affect your 
baby. 
If you can get pregnant, you and your partner must use an effective method of contraception while 
using MabThera. You must also do this for 12 months after your last treatment with MabThera. 
Do not breast-feed while you are being treated with MabThera. Also do not breast-feed for 12 months 
after your last treatment with MabThera. This is because MabThera may pass into breast milk. 
 
Driving and using machines 
It is not known whether MabThera has an effect on you being able to drive or use any tools or 
machines. 
 
Sodium 
MabThera 1400 mg contains less than 1 mmol sodium (main component of the cooking/table salt) per 
dose, i.e. it is essentially sodium-free. 
 
 



138 

3 How MabThera is given 
 
How it is given 
MabThera will be given to you by a doctor or nurse who is experienced in the use of this treatment. 
They will watch you closely while you are being given this medicine. This is in case you get any side 
effects. 
 
You will always be given MabThera as a drip (intra-venous infusion) at the start of your treatment.  
 
After this, you will be given MabThera as an injection under your skin (subcutaneous injection) over 
approximately 5 minutes. There is a peel-off sticker on the glass vial that specifies the medication. 
Your doctor or nurse will place the sticker on the syringe before injection.   
 
Your doctor will decide when to start MabThera injections. 
 
When injected under your skin, it is given in the stomach area, not in other sites of the body, and not 
into areas of the stomach where the skin is red, bruised, tender, hard or where there are moles or scars. 
 
Medicines given before each MabThera administration 
Before you are given MabThera, you will be given other medicines (pre-medication) to prevent or 
reduce possible side effects. 
 
How much and how often you will receive your treatment 

 
• MabThera will be given to you on the same day as your chemotherapy. This is usually given 

every 3 weeks up to 8 times. 
• If you respond well to treatment, you may be given MabThera as a maintenance treatment 

every 2 or 3 months for two years.  
 Your doctor may change this, depending on how you respond to the medicine. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4 Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Most side effects are mild to moderate but some may be serious and need treatment. Rarely, some of 
these side effects have been fatal. 
 
Reactions where the medicine is injected 
Many patients get some local side effects where MabThera is injected. These include: pain, swelling, 
bruising, bleeding, skin redness, itching and rash.  
Your doctor may decide to stop your MabThera treatment if these reactions are serious. 
 
Infections 
Tell your doctor immediately if you get signs of an infection including: 
• fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell 
• memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare, 

serious brain infection, which has been fatal (Progressive Multifocal Leukoencephalopathy or 
PML). 

You might get infections more easily during your treatment with MabThera. These are often colds, but 
there have been cases of pneumonia or urinary infections. These are listed below under “Other side 
effects”. 
 



139 

Other side effects include: 
 
Very common side effects (may affect more than 1 in 10 people): 
• bacterial or viral infections, bronchitis 
• low number of white blood cells with or without fever or blood cells called “platelets” 
• feeling sick (nausea) 
• bald spots on the scalp, chills, headache 
• lower immunity – because of lower levels of anti-bodies called “immunoglobulins” (IgG) in the 

blood which help protect against infection. 
 
Common side effects (may affect up to 1 in 10 people): 
• infections of the blood (sepsis), pneumonia, shingles, cold, bronchial tube infections, fungal 

infections, infections of unknown origin, sinus inflammation, hepatitis B 
• low number of red blood cells (anaemia), low number of all blood cells  
• allergic reactions (hypersensitivity),  
• high blood sugar level, weight loss, swelling in the face and body, high levels of the enzyme 

“LDH” in the blood, low calcium levels in the blood 
• unusual feelings of the skin – such as numbness, tingling, pricking, burning, a creeping skin 

feeling, reduced sense of touch 
• feeling restless, problems falling asleep 
• becoming very red in the face and other areas of the skin as a consequence of dilation of the 

blood vessels 
• feeling dizzy or anxious 
• producing more tears, tear duct problems, inflamed eye (conjunctivitis) 
• ringing sound in the ears, ear pain 
• heart problems – such as heart attack, uneven or fast heart rate 
• high or low blood pressure (low blood pressure especially when standing upright) 
• tightening of the muscles in the airways which causes wheezing (bronchospasm), inflammation, 

irritation in the lungs, throat or sinuses, being short of breath, runny nose 
• being sick (vomiting), diarrhoea, pain in the stomach, irritation or ulcers in the throat and 

mouth, problems swallowing, constipation, indigestion 
• eating disorders, not eating enough, leading to weight loss 
• hives, increased sweating, night sweats 
• muscle problems – such as tight muscles, joint or muscle pain, back and neck pain 
• tumour pain 
• general discomfort or feeling uneasy or tired, shaking, signs of flu 
• multiple-organ failure. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
• blood clotting problems, decrease of red blood cell production and increase of red blood cell 

destruction (aplastic haemolytic anaemia), swollen or enlarged lymph nodes 
• low mood and loss of interest or enjoyment in doing things, feeling nervous 
• taste problems – such as changes in the way things taste 
• heart problems – such as reduced heart rate or chest pain (angina) 
• asthma, too little oxygen reaching the body organs 
• swelling of the stomach. 
 
Very rare side effects (may affect up to 1 in 10, 000 people): 
• short term increase in the amount of some types of anti-bodies in the blood (called 

immunoglobulins – IgM), chemical disturbances in the blood caused by break-down of dying 
cancer cells 

• nerve damage in arms and legs, paralysed face 
• heart failure 
• inflammation of blood vessels including those leading to skin symptoms 
• respiratory failure 



140 

• damage to the intestinal wall (perforation) 
• severe skin problems causing blisters that can be life-threatening  
• kidney failure 
• Severe vision loss (sign of brain nerves damage). 
 
Not known (it is not known how often these side effects happen): 
• a reduction in white blood cells which does not happen straight away 
• reduced platelets number just after the infusion – this can be reversed, but can be fatal in rare 

cases 
• hearing loss, loss of other senses.  
 
MabThera may also cause changes in laboratory tests carried out by your doctor.  
 
If you are having MabThera with other medicines, some of the side effects you may get may be due to 
the other medicines. 
 
Reporting of side effects 
If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5 How to store MabThera 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2 °C to 8 °C). Do not freeze. Keep the container in the outer carton in order to 
protect from light. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6 Contents of the pack and other information 
 
What MabThera 1400 mg solution for subcutaneous injection contains 
• The active ingredient is rituximab. Each vial contains 1400 mg/11.7 mL of rituximab. 

Each mL contains 120 mg of rituximab. 
 
• The other ingredients are recombinant human hyaluronidase (rHuPH20), L-histidine, L-histidine 

hydrochloride monohydrate, α,α-trehalose dihydrate, L-methionine, polysorbate 80 and water for 
injections. 

 
What MabThera 1400 mg solution for subcutaneous injection looks like and contents of the pack 
MabThera is a ready to use, clear to opalescent, colourless to yellowish liquid, supplied as a solution 
for subcutaneous injection in a colourless glass vial with a butyl rubber stopper with aluminium over 
seal and a pink plastic flip-off disk.  
 
Each vial contains 1400 mg/11.7 mL of rituximab. Each carton contains one vial.  
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


141 

Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
Roche Pharma AG 
Emil-Barell-Str. 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark 
Roche a/s  
Tlf: +45 - 36 39 99 99 
 

Malta 
(See Ireland) 
  

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33  (0)1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: + 385 1 47 22 333 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 



142 

Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.ema.europa.eu.  
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 
  

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


143 

Package leaflet: Information for the patient  
 

MabThera 1600 mg solution for subcutaneous injection  
rituximab  

 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What MabThera is and what it is used for 
2. What you need to know before you are given MabThera  
3. How MabThera is given 
4. Possible side effects 
5. How to store MabThera  
6. Contents of the pack and other information 
 
 
1. What MabThera is and what it is used for 
 
What MabThera is 
MabThera contains the active substance “rituximab”. This is a type of protein called a “monoclonal 
antibody”. It sticks to the surface of a type of white blood cell called “B-Lymphocyte”. When 
rituximab sticks to the surface of this cell, the cell dies. 
MabThera is available as a medicine given as a drip (called MabThera 100 mg or MabThera 500 mg, 
concentrate for solution for infusion) and as a medicine for injection under your skin: called MabThera 
1400 mg or MabThera 1600 mg, solution for subcutaneous injection). 
 
What MabThera is used for 
MabThera 1600 mg is used to treat chronic lymphocytic leukaemia -in adults. 
• Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL 

affects a type of white blood cell called B-lymphocytes, which originates from the bone marrow 
and develops in the lymph nodes. Patients with CLL have too many abnormal lymphocytes, 
which accumulate mainly in the bone marrow and blood. The proliferation of these abnormal 
B-lymphocytes is the cause of symptoms you may have. 

 MabThera in combination with chemotherapy destroys these cells which are gradually removed 
from the body by biological processes-. 

 
You will be given MabThera 1600 mg with other medicines called “chemotherapy”.  
You will always be given MabThera as a drip (intra-venous infusion) at the start of your treatment.  
 
After this, you will be given MabThera as an injection under your skin. Your doctor will decide when 
to start MabThera injections. 
 
 
2 What you need to know before you are given MabThera 
 
Do not have MabThera if: 
• you are allergic to rituximab, other proteins which are like rituximab, or any of the other 

ingredients of this medicine (listed in section 6) 
• you are allergic to hyaluronidase (an enzyme that helps to increase the absorption of injected 

active substance)  
• you have a severe active infection at the moment 



144 

• you have a weak immune system. 
 
Do not have MabThera if any of the above apply to you. If you are not sure, talk to your doctor, 
pharmacist or nurse before you are given MabThera. 
  
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before you are given MabThera if: 
• you have ever had or might now have a hepatitis infection. This is because in a few cases, 

MabThera could cause hepatitis B to become active again, which can be fatal in very rare cases. 
Patients who have ever had hepatitis B infection will be carefully checked by their doctor for 
signs of this infection 

• you have ever had heart problems (such as angina, palpitations or heart failure) or breathing 
problems.  

 
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
you are given MabThera. Your doctor may need to take special care of you during your treatment with 
MabThera. 
 
Children and adolescents 
Talk to your doctor, pharmacist or nurse before you are given this medicine if you, or your child, are 
under 18 years of age. This is because there is not much information about the use of MabThera in 
children and adolescents. 
 
Other medicines and MabThera  
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription and herbal medicines. This is 
because MabThera can affect the way some other medicines work. Also some other medicines can 
affect the way MabThera works.  
 
In particular, tell your doctor: 
• if you are taking medicines for high blood pressure. You may be asked not to take these other 

medicines 12 hours before you are given MabThera. This is because some people have a fall in 
their blood pressure while they are being given MabThera 

• if you have ever taken medicines which affect your immune system – such as chemotherapy or 
immune-suppressive medicines. 

 
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
you are given MabThera. 
 
Pregnancy and breast-feeding  
You must tell your doctor or nurse if you are pregnant, think that you might be pregnant or are 
planning to become pregnant. This is because MabThera can cross the placenta and may affect your 
baby. 
If you can get pregnant, you and your partner must use an effective method of contraception while 
using MabThera. You must also do this for 12 months after your last treatment with MabThera. 
Do not breast-feed while you are being treated with MabThera. Also do not breast-feed for 12 months 
after your last treatment with MabThera. This is because MabThera may pass into breast milk. 
 
Driving and using machines 
It is not known whether MabThera has an effect on you being able to drive or use any tools or 
machines. 
 
Sodium 
MabThera 1600 mg contains less than 1 mmol sodium (main component of the cooking/table salt) per 
dose, i.e. it is essentially sodium-free. 
 
 



145 

3 How MabThera is given 
 
How it is given 
MabThera will be given to you by a doctor or nurse who is experienced in the use of this treatment. 
They will watch you closely while you are being given this medicine. This is in case you get any side 
effects. 
 
You will always be given MabThera as a drip (intra-venous infusion) at the start of your treatment.  
 
After this, you will be given MabThera as an injection under your skin (subcutaneous injection) over 
approximately 7 minutes. There is a peel-off sticker on the glass vial that specifies the medication. 
Your doctor or nurse will place the sticker on the syringe before injection.   
 
Your doctor will decide when to start MabThera injections. 
 
When injected under your skin, it is given in the stomach area, not in other sites of the body, and not 
into areas of the stomach where the skin is red, bruised, tender, hard or where there are moles or scars. 
 
Medicines given before each MabThera administration 
Before you are given MabThera, you will be given other medicines (pre-medication) to prevent or 
reduce possible side effects. 
 
How much and how often you will receive your treatment 

 
When you are treated with MabThera in combination with chemotherapy, you will receive a 
MabThera infusion on day 0 of cycle 1, then subcutaneous injections on day 1 of each subsequent 
cycle. The total number of cycles is of 6. Each cycle has a duration of 28 days. The chemotherapy 
should be given after the MabThera administration. 
 
Your doctor will decide if you should receive concomitant supportive therapy. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4 Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Most side effects are mild to moderate but some may be serious and need treatment. Rarely, some of 
these side effects have been fatal. 
 
Reactions where the medicine is injected 
Many patients get some local side effects where MabThera is injected. These include: pain, swelling, 
bruising, bleeding, skin redness, itching and rash.  
 
Your doctor may decide to stop your MabThera treatment if these reactions are serious. 
Infections 
Tell your doctor immediately if you get signs of an infection including: 
• fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell 
• memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare, 

serious brain infection, which has been fatal (Progressive Multifocal Leukoencephalopathy or 
PML). 

You might get infections more easily during your treatment with MabThera. These are often colds, but 
there have been cases of pneumonia or urinary infections. These are listed below under “Other side 
effects”. 
 



146 

Other side effects include: 
 
Very common side effects (may affect more than 1 in 10 people): 
• bacterial or viral infections, bronchitis 
• low number of white blood cells with or without fever or blood cells called “platelets” 
• feeling sick (nausea) 
• bald spots on the scalp, chills, headache 
• lower immunity – because of lower levels of anti-bodies called “immunoglobulins” (IgG) in the 

blood which help protect against infection. 
 
Common side effects (may affect up to 1 in 10 people): 
• infections of the blood (sepsis), pneumonia, shingles, cold, bronchial tube infections, fungal 

infections, infections of unknown origin, sinus inflammation, hepatitis B 
• low number of red blood cells (anaemia), low number of all blood cells  
• allergic reactions (hypersensitivity),  
• high blood sugar level, weight loss, swelling in the face and body, high levels of the enzyme 

“LDH” in the blood, low calcium levels in the blood 
• unusual feelings of the skin – such as numbness, tingling, pricking, burning, a creeping skin 

feeling, reduced sense of touch 
• feeling restless, problems falling asleep 
• becoming very red in the face and other areas of the skin as a consequence of dilation of the 

blood vessels 
• feeling dizzy or anxious 
• producing more tears, tear duct problems, inflamed eye (conjunctivitis) 
• ringing sound in the ears, ear pain 
• heart problems – such as heart attack, uneven or fast heart rate 
• high or low blood pressure (low blood pressure especially when standing upright) 
• tightening of the muscles in the airways which causes wheezing (bronchospasm), inflammation, 

irritation in the lungs, throat or sinuses, being short of breath, runny nose 
• being sick (vomiting), diarrhoea, pain in the stomach, irritation or ulcers in the throat and 

mouth, problems swallowing, constipation, indigestion 
• eating disorders, not eating enough, leading to weight loss 
• hives, increased sweating, night sweats 
• muscle problems – such as tight muscles, joint or muscle pain, back and neck pain 
• tumour pain 
• general discomfort or feeling uneasy or tired, shaking, signs of flu 
• multiple-organ failure. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
• blood clotting problems, decrease of red blood cell production and increase of red blood cell 

destruction (aplastic haemolytic anaemia), swollen or enlarged lymph nodes 
• low mood and loss of interest or enjoyment in doing things, feeling nervous 
• taste problems – such as changes in the way things taste 
• heart problems – such as reduced heart rate or chest pain (angina) 
• asthma, too little oxygen reaching the body organs 
• swelling of the stomach. 
 
Very rare side effects (may affect up to 1 in 10, 000 people): 
• short term increase in the amount of some types of anti-bodies in the blood (called 

immunoglobulins – IgM), chemical disturbances in the blood caused by break-down of dying 
cancer cells 

• nerve damage in arms and legs, paralysed face 
• heart failure 
• inflammation of blood vessels including those leading to skin symptoms 
• respiratory failure 



147 

• damage to the intestinal wall (perforation) 
• severe skin problems causing blisters that can be life-threatening  
• kidney failure 
• Severe vision loss (sign of brain nerves damage). 
 
Not known (it is not known how often these side effects happen): 
• a reduction in white blood cells which does not happen straight away 
• reduced platelets number just after the infusion – this can be reversed, but can be fatal in rare 

cases 
• hearing loss, loss of other senses.  
 
MabThera may also cause changes in laboratory tests carried out by your doctor.  
 
If you are having MabThera with other medicines, some of the side effects you may get may be due to 
the other medicines. 
 
Reporting of side effects 
If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5 How to store MabThera 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2 °C to 8 °C). Do not freeze. Keep the container in the outer carton in order to 
protect from light. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6 Contents of the pack and other information 
 
What MabThera 1600 mg solution for subcutaneous injection contains 
• The active ingredient is rituximab. Each vial contains 1600  mg/13.4 mL of rituximab. 

Each mL contains 120 mg of rituximab. 
 
• The other ingredients are recombinant human hyaluronidase (rHuPH20), L-histidine, L-histidine 

hydrochloride monohydrate, α,α-trehalose dihydrate, L-methionine, polysorbate 80 and water for 
injections. 

 
What MabThera 1600  mg solution for subcutaneous injection looks like and contents of the 
pack 
MabThera is a ready to use, clear to opalescent, colourless to yellowish liquid, supplied as a solution 
for subcutaneous injection in a colourless glass vial with a butyl rubber stopper with aluminium over 
seal and a blue plastic flip-off disk.  
 
Each vial contains 1600 mg/13.4 mL of rituximab. Each carton contains one vial.  
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


148 

Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
Roche Pharma AG 
Emil-Barell-Str. 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark 
Roche a/s  
Tlf: +45 - 36 39 99 99 
 

Malta 
(See Ireland) 
 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33  (0)1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: + 385 1 47 22 333 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 



149 

Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.ema.europa.eu.  
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 

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

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