Blitzima

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ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Blitzima 100 mg concentrate for solution for infusion 

Blitzima 500 mg concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Blitzima 100mg concentrate for solution for infusion 

Each mL contains 10 mg of rituximab. 

Each 10mL vial contains 100 mg of rituximab. 

 

Blitzima 500mg concentrate for solution for infusion 

Each mL contains 10 mg of rituximab. 

Each 50mL 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 10mL vial contains 2.3 mmol (52. 6mg) sodium. 

Each 50mL 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 6.3 – 6.8 and osmolality of 329 - 387 mOsmol/kg. 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Blitzima is indicated in adults for the following indications:  

 

Non-Hodgkin’s lymphoma (NHL) 

 

Blitzima is indicated for the treatment of previously untreated adult patients with stage III-IV 

follicular lymphoma in combination with chemotherapy. 

 

Blitzima maintenance therapy is indicated for the treatment of adult follicular lymphoma 

patients responding to induction therapy. 

 

Blitzima monotherapy is indicated for treatment of adult patients with stage III-IV follicular 

lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy. 

 

Blitzima is indicated for the treatment of adult patients with CD20 positive diffuse large B cell 



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non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, 

prednisolone) chemotherapy. 

 

Blitzima in combination with chemotherapy is indicated for the treatment of paediatric patients 

(aged ≥ 6 months  to < 18 years old) with previously untreated advanced stage CD20 positive 

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) 

 

Blitzima 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 Blitzima or patients refractory to 

previous Blitzima plus chemotherapy. 

 

See section 5.1 for further information. 

 

Granulomatosis with polyangiitis and microscopic polyangiitis 

 

Blitzima, in combination with glucocorticoids, is indicated for the treatment of adult patients with 

severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis 

(MPA). 

 

Blitzima, 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 

 

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

 

4.2 Posology and method of administration 

 

Blitzima 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 Blitzima. 

 

In adult patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should 

be considered if Blitzima 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 Blitzima. In addition, prednisone should be given as indicated in Table 1. 

 

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start 

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 Blitzima to decrease the rate 

and severity of acute infusion reactions and/or cytokine release syndrome. 

 

In patients with GPA or MPA in disease remission or pemphigus vulgaris, premedication with 100 

mg intravenous methylprednisolone should be completed 30 minutes prior to each infusion of 

Blitzima to decrease the incidence and severity of infusion related reactions (IRRs). 

 



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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 Blitzima (the last dose of 

methylprednisolone may be given on the same day as the first infusion of Blitzima). 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 Blitzima treatment. 

 

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

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

practice guidelines. 

 

Paediatric population 

In paediatric patients with GPA or MPA, prior to the first Blitzima 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 Blitzima 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 Blitzima treatment, as appropriate. 

 

Posology 

 

Non-Hodgkin’s lymphoma 

 

Follicular non-Hodgkin's lymphoma 

 

Combination therapy 

The recommended dose of Blitzima 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. 

 

Blitzima 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 Blitzima 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). 

 

• Relapsed/refractory follicular lymphoma 

The recommended dose of Blitzima 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 Blitzima 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. 

 



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For retreatment with Blitzima monotherapy for patients who have responded to previous treatment 

with Blitzima 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 

 

Blitzima 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 Blitzima 

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 Blitzima are recommended. When Blitzima is given in combination with 

chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be 

applied. 

 

Chronic lymphocytic leukaemia 

 

The recommended dosage of Blitzima 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 Blitzima infusion. 

 

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 

 

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

 

Adult induction of remission 

The recommended dosage of Blitzima 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 Blitzima, maintenance treatment in adult patients with 

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

 

Following induction of remission with other standard of care immunosuppressants, Blitzima 

maintenance treatment should be initiated during the 4 week period that follows disease 

remission.  

 

Blitzima 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 Blitzima 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 Blitzima 

maintenance therapy, up to 5 years. 

 

Pemphigus vulgaris 

 

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

 

The recommended dosage of Blitzima 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. 

 



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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 

 

Elderly 

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

 

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, Blitzima should be used in combination with systemic 

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

Blitzima is 375mg/m2 BSA, administered as an IV infusion. No Blitzima dose adjustments, other than 

by BSA, are required. 

 

The safety and efficacy of Blitzima 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.  

 

Blitzima 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 Blitzima administration for Non-Hodgkin’s lymphoma paediatric 

patients 

Cycle Day of treatment Administration details 

Prephase (COP) No Blitzima given - 

Induction course 1 

(COPDAM1) 

Day -2 

(corresponding to day 6 

of the prephase) 

1st Blitzima infusion 

 

During the 1st induction course, prednisone is 

given as part of the chemotherapy course, and 

should be administered prior to Blitzima. 

Day 1 

2nd Blitzima infusion 

 

Blitzima will be given 48 hours after thefirst 

infusion of Blitzima. 

Induction course 2 

(COPDAM2) 

Day -2 

3rd Blitzima infusion 

 

In the 2nd induction course, prednisone is not 

given at the time of Blitzima administration. 

Day 1 

4th Blitzima infusion 

 

Blitzima will be given 48 hours after the third 

infusion of Blitzima. 

Consolidation 

course 1 

(CYM/CYVE) 

Day 1 

5th Blitzima infusion 

 

Prednisone is not given at the time of Blitzima 

administration. 

Consolidation 

course 2 

Day 1 

6th Blitzima infusion 

 



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(CYM/CYVE) Prednisone is not given at the time of Blitzima 

administration. 

Maintenance 

course 1 (M1) 

Day 25 to 28 of 

consolidation course 2 

(CYVE) 

No Blitzima 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 Blitzima given 

- 

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

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

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

 

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

Chemotherapy with Blitzima  

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 Blitzima 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 Blitzima in paediatric patients (≥ 2 to < 18 years of age) has not been 

established in indications other than severe, active GPA or MPA. 

 

Blitzima 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). 

 

Method of administration 

 

The prepared Blitzima 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 



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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 (IRRs) (section 4.8) usually respond to a 

reduction in the rate of infusion. The infusion rate may be increased upon improvement of 

symptoms. 

 

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 Blitzima 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 Blitzima 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. 

 

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. 

 

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). 



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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 (or stated) in the patient file. 

 

Progressive multifocal leukoencephalopathy (PML) 

 

All patients treated with rituximab 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 PML. 

 

Very rare cases of fatal PML have been reported following the use of rituximab. 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 rituximab must be permanently discontinued.  

 

Following reconstitution of the immune system in immunocompromised patients with PML, 

stabilisation or improved outcome has been seen. It remains unknown if early detection of PML 

and suspension of rituximab therapy may lead to similar stabilisation or improved outcome. 

 

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia 

 

Infusion-related reactions 

Rituximab 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. 

 

Severe infusion-related reactions with fatal outcome have been reported during post-marketing use 

of the rituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours after 

starting the first rituximab 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). 

 

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 



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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 

rituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in 

10% of patients) see section 4.8. These symptoms are usually reversible with interruption of 

rituximab 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 

rituximab. 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 rituximab administration, consideration should be given to 

withholding anti-hypertensive medicines 12 hours prior to the rituximab 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 rituximab. Therefore, patients with a 

history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. 

 

Haematological toxicities 

Although rituximab 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. Rituximab 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 

rituximab therapy. 

 

Infections 

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

Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, 



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sepsis and opportunistic infections, see section 4.3). 

 

Physicians should exercise caution when considering the use of rituximab 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 rituximab 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 

rituximab treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus 

(HBV) screening should be performed in all patients before initiation of treatment with rituximab. 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 rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb) 

should consult liver disease experts before start of treatment and should be monitored and 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 rituximab in NHL and CLL (see section 4.8). The majority of patients had 

received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell 

transplant. 

 

Immunisations 

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

studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. 

Patients treated with rituximab 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 rituximab 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 rituximab. 

 

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 rituximab, 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. 

 

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

pemphigus vulgaris 

 

Methotrexate (MTX) naïve populations with rheumatoid arthritis 

The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit risk 

relationship has not been established. 

 

Infusion-related reactions 

Rituximab 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 



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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 rituximab 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 rituximab. 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 rituximab. 

 

There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III) 

or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence 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 rituximab 

and patients closely monitored during administration. Since hypotension may occur during rituximab 

infusion, consideration should be given to withholding anti-hypertensive medicinal product 12 hours 

prior to the rituximab 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 rituximab. Therefore patients with 

a history of cardiac disease should be monitored closely (see Infusion-related reactions, above). 

 

Infections 

Based on the mechanism of action of rituximab and the knowledge that B cells play an important 

role in maintaining normal immune response, patients have an increased risk of infection following 

rituximab therapy (see section 5.1). Serious infections, including fatalities, can occur during therapy 

with rituximab (see section 4.8). Rituximab should not be administered to patients with an active, 

severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely 

immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should 

exercise caution when considering the use of rituximab 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 rituximab. 

 

Patients reporting signs and symptoms of infection following rituximab therapy should be promptly 

evaluated and treated appropriately. Before giving a subsequent course of rituximab treatment, 

patients should be re-evaluated for any potential risk for infections. 

 

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported 

following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases 

including Systemic Lupus Erythematosus (SLE) and vasculitis. 

 

Hepatitis B Infections 



13  

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in 

rheumatoid arthritis, GPA and MPA patients receiving rituximab. 

 

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment 

with rituximab. At minimum this should include HBsAg-status and HBcAb-status. These can be 

complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B 

disease should not be treated with rituximab. Patients with positive hepatitis B serology (either 

HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be 

monitored and managed following local medical standards to prevent hepatitis B reactivation. 

 

Late neutropenia 

Measure blood neutrophils prior to each course of rituximab, 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 rituximab, 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 rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration 

of rituximab. 

 

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

Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst 

peripherally B cell depleted. 

 

Patients treated with rituximab 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 

rituximab 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 rituximab as 

compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst 

receiving rituximab therapy, these should be completed at least 4 weeks prior to commencing the next 

course of rituximab. 

 

In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, 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 rituximab 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 rituximab (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 rituximab, however patients should be closely 

observed for signs of infection if biologic agents and/or DMARDs are used following rituximab 

therapy. 

 

Malignancy 

Immunomodulatory medicinal products may increase the risk of malignancy. On the basis of 

limited experience with rituximab in rheumatoid arthritis patients (see section 4.8) the present data 



14  

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 rituximab. 

 

In CLL patients, co-administration with rituximab 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 rituximab. 

 

Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab 

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 rituximab. In these patients the rate of clinically relevant infection while on 

rituximab 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 rituximab. 

 

Pregnancy 

 

IgG immunoglobulins are known to cross the placental barrier. 

B cell levels in human neonates following maternal exposure to rituximab 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 rituximab during pregnancy. Similar effects have been observed in animal studies 

(see section 5.3). For these reasons rituximab should not be administered to pregnant women 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 rituximab and for 12 months following rituximab treatment. 

 

Fertility 

 

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

 



15  

4.7 Effects on ability to drive and use machines 

 

No studies on the effects of rituximab on the ability to drive and use machines have been performed, 

although the pharmacological activity and adverse reactions reported to date suggest that rituximab 

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 adult 

 

Summary of the safety profile 

 

The overall safety profile of rituximab 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 rituximab monotherapy (as induction treatment or maintenance treatment following induction 

treatment) or in combination with chemotherapy. 

 

The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab 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 rituximab. 

 

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 frequent reported or observed serious adverse drug reactions were: 

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

 Infections, see section 4.4. 

 Cardiovascular events, see section 4.4. 

 

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

 

Tabulated list of adverse reactions 

 

The frequencies of ADRs reported with rituximab 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 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 post-marketing surveillance in  

patients with NHL and CLL disease treated with rituximab 

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, 

 serious viral 

infection2 

pneumocystis 

jirovecii 

PML  



16  

infections of 

unknown 

aetiology, 
+acute 

bronchitis, 
+sinusitis, 

hepatitis B1 

Blood and 

lymphatic 

system 

disorders 

neutropenia, 

leucopenia, 
+febrile 

neutropenia, 
+thrombocyto

penia 

anaemia, 
+pancytopenia, 
+granulocytope

nia 

coagulation 

disorders, 

aplastic 

anaemia, 

haemolytic 

anaemia, 

lymphadenop

athy 

 transient 

increase in 

serum IgM 

levels3 

late 

neutropenia3 

Immune 

system 

disorders 

infusion-relate

d reactions4, 

angioedema 

hypersensitivity  anaphylaxis tumour lysis 

syndrome, 

cytokine 

release 

syndrome4, 

serum 

sickness 

infusion-relate

d acute 

reversible 

thrombocytop

enia4 

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, 
+supraventri-

cular 

tachycardia, 

+ventricular 

tachycardia, 

+angina, 

+myocardial 

ischaemia, 

bradycardia 

severe cardiac 

disorders4 and 6 

heart failure4 

and 6 

 

Vascular 

disorders 
 hypertension, 

orthostatic 

hypotension, 

hypotension 

  vasculitis 

(predominatel

y cutaneous), 

leukocytoclast

ic 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 



17  

Gastrointesti

nal disorders 

nausea vomiting , 

diarrhoea, 

abdominal pain, 

dysphagia, 

stomatitis, 

constipation, 

dyspepsia, 

anorexia, throat 

irritation 

abdominal 

enlargement 

 gastro-intestin

al 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 

 

Musculoskele

tal, 

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 

   

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 rituximab 

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 rituximab-arms compared to control 

arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, 

pyrexia. 

 

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% 

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, 



18  

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 rituximab-containing 

treatment. 

 

Description of selected adverse reactions 

 

Infections 

Rituximab 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 rituximab-containing arm of randomised studies. Severe infections were reported in about 

4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall, 

including grade 3 or 4 infections, were observed during rituximab 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 

rituximab treatment. The majority of patients had received rituximab 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 (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 rituximab 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 rituximab-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 rituximab 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 rituximab 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 rituximab in combination with 

chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), 

neutropenia (R-CVP 24% vs. CVP 14%; R-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 rituximab 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 

rituximab 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 rituximab 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. 



19  

 

In studies of rituximab 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 rituximab 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 rituximab 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 rituximab compared to < 1% on 

observation. In studies evaluating rituximab 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 rituximab 

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. 

 

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 

rituximab for treatment of non-Hodgkin’s lymphoma. In the majority of these cases, rituximab was 

administered with chemotherapy. 

 

IgG levels 

In the clinical trial evaluating rituximab 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 rituximab groups. In the observation group, the median IgG 

level subsequently increased to above the LLN, but remained constant in the rituximab group. The 

proportion of patients with IgG levels below the LLN was about 60% in the rituximab group 

throughout the 2 year treatment period, while it decreased in the observation group (36% after 



20  

2 years). 

 

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been 

observed in paediatric patients treated with rituximab, 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’s syndrome) and Stevens-Johnson syndrome, some with fatal 

outcome, have been reported very rarely. 

 

Patient subpopulations - rituximab 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 rituximab was 

similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 

ADRs). 

 

Patient subpopulations - rituximab 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 rituximab 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 rituximab and were included in the safety analysis 

population. Paediatric patients randomized to the LMB chemotherapy arm with rituximab, or enrolled 

in the single arm part of the study, were administered rituximab at a dose of 375mg/m2 BSA and 

received a total of six IV infusions of rituximab (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 rituximab 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 

rituximab 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 rituximab in rheumatoid arthritis is based on data from patients from 



21  

clinical trials and from post-marketing surveillance. 

 

The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) is 

summarised in the sections below. In clinical trials more than 3,100 patients received at least one 

treatment course and were followed for periods ranging from 6 months to over 5 years; 

approximately 2,400 patients received two or more courses of treatment with over 1,000 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 rituximab (see section 4.4). 

 

Patients received 2 x 1,000 mg of rituximab separated by an interval of two weeks; in addition to 

methotrexate (10-25 mg/week). Rituximab 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 rituximab 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 initial course. In addition to adverse reactions seen in RA clinical trials for rituximab, 

progressive multifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like 

reaction have been reported during post marketing experience. 

 
Table 4 Summary of adverse drug reactions reported in clinical trials or during 

post-marketing surveillance occurring in patients with rheumatoid arthritis 

receiving rituximab 
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 

pedís 

  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, erythma) 

 3infusion-related 

reactions 

(generalised 

oedema, 

bronchospasm, 

wheezing, 

laryngeal 

oedema, 

angioneurotic 

oedema, 

generalised 

pruritis, 

anaphylaxis, 

anaphylactoid 

reaction) 

  

General disorders 

and 

administration site 

conditions 

Metabolism and 

nutritional 

disorders 

 hypercholesterolemia    

Psychiatric 

disorders 

 depression, anxiety    

Nervous system 

disorders 

headache paraesthesia, 

migraine, dizziness, 

sciatica 

   



22  

MedDRA 

System Organ 

Class 

Very 

Common 
Common Uncommon Rare Very rare 

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 

 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 

 

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 rituximab 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 rituximab in clinical studies were IRRs (refer to Table 

4). Among the 3189 patients treated with rituximab, 1,135 (36%) experienced at least one IRR with 

733/3,189 (23%) of patients experiencing an IRR following first infusion of the first exposure to 

rituximab. 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 rituximab 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 rituximab. 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 rituximab treated 



23  

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 rituximab. Lower respiratory 

tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence 

in the rituximab-arms compared to control arms. 

 

Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported 

following use of rituximab for the treatment of autoimmune diseases. This includes rheumatoid 

arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and 

vasculitis. 

 

In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with 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 rheumatoid arthritis patients 

receiving rituximab (see section 4.4). 

 

Cardiovascular adverse reactions 

Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the rituximab 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. 

 

Neutropenia 

Events of neutropenia were observed with rituximab treatment, the majority of which were 

transient and mild or moderate in severity. Neutropenia can occur several months after the 

administration of rituximab (see section 4.4). 

 

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and 

0.27% (2/731) of placebo-treated patients developed severe neutropenia. 

 

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported 

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 rituximab. 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 rituximab, 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) 

 



24  

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 rituximab (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1). 

 

Tabulated list of adverse reactions 

 

The ADRs listed in Table 5 were all adverse events which occurred at an incidence of ≥ 5% in the 

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

 

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

receiving rituximab in GPA/MPA Study 1, and at a higher frequency than 

the comparator group, in the pivotal clinical study. 

MedDRA System Organ Class 
Adverse event 

Rituximab (n=99) 

Infections and infestations 

Urinary tract infection 7% 

Bronchitis 5% 

Herpes zoster 5% 

Nasopharyngitis 5% 

Blood and lymphatic  

system disorders 

Thrombocytopenia 7% 

Immune system disorders 

Cytokine release syndrome 5% 

Metabolism and nutrition disorders 

Hyperkalaemia 5% 

Psychiatric disorders 

Insomnia 14% 

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% 



25  

MedDRA System Organ Class 
Adverse event 

Rituximab (n=99) 

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 

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

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

in GPA/MPA Study 2, and at a higher frequency than the comparator group 

MedDRA System Organ Class 

Adverse drug reaction 

Rituximab  

(n=57) 

Infections and infestations   

Bronchitis 14% 

Rhinitis 5% 

General disorders and administration site 

conditions 
 

Pyrexia 9% 

Influenza-like illness 5% 

Oedema peripheral 5% 

Gastrointestinal disorders   

Diarrhoea 7% 

Respiratory, thoracic and mediastinal 

disorders 
 

Dyspnoea 9% 

Injury, poisoning and procedural 

complications 
 

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

section. 

 
The overall safety profile was consistent with the well-established safety profile for rituximab in 

approved autoimmune indications, including GPA and MPA. Overall, 4% of patients in the rituximab 

arm experienced adverse events leading to discontinuation. Most adverse events in the rituximab arm 

were mild or moderate in intensity. No patients in the rituximab arm had fatal adverse events. 

 

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

infections.   

 

Long-term follow-up (GPA/MPA Study 3) 

In a long-term observational safety study, 97 GPA and MPA patients received treatment with 

rituximab (mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician’s standard 

practice and discretion. The overall safety profile was consistent with the well-established safety 

profile of rituximab in RA and GPA and MPA and no new adverse drug reactions were reported. 

 



26  

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, rituximab was given at the 

discretion of the investigator (17 out of 25 patients received additional rituximab treatment).  

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

 

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

infections (17 patients [68%] in the remission induction phase; 23 patients [92%] in the overall 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 rituximab was consistent with that reported 

during the remission induction phase.  

 

The safety profile of rituximab 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 drug 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 rituximab, 12 (12%) experienced at least one 

IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release 

syndrome, flushing, throat irritation, and tremor. Rituximab was given in combination with 

intravenous glucocorticoids which may reduce the incidence and severity of these events. 

 

In GPA/MPA Study 2 (adult maintenance study), 7/57 (12%) patients in the rituximab 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%).  

 

 

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 rituximab 

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 rituximab.  The majority of IRRs were Grade 1 and 

Grade 2, there were two non-serious Grade 3 IRRs, and no Grade 4 or 5 IRRs reported.  One serious 

Grade 2 IRR (generalized oedema which resolved with treatment) was reported in one patient (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 rituximab group was pneumonia at a frequency of 4%. 

 

In GPA/MPA Study 2, 30/57 (53%) patients in the rituximab arm experienced infections. The 

incidence of all grade infections was similar between the arms. Infections were predominately mild 

to moderate. The most common infections in the rituximab arm included upper respiratory tract 

infections, gastroenteritis, urinary tract infections and herpes zoster. The incidence of serious 

infections was similar in both arms (approximately 12%). The most commonly reported serious 



27  

infection in the rituximab group was mild or moderate bronchitis. 

 

In the clinical trial in paediatric patients with severe, active GPA and MPA, 91% of reported 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. 

 

Malignancies 

In GPA/MPA Study 1, the incidence of malignancy in rituximab 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 rituximab in the post-

marketing setting. 

 

Hypogammaglobulinaemia 

Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in 

adult and peadiatric GPA and MPA patients treated with rituximab.  

 

In GPA/MPA Study 1, at 6 months, in the rituximab group, 27%, 58% and 51% of patients with 

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, 



28  

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 rituximab 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 rituximab-treated patients.  

 

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

vs. 5% for azathioprine treated patients. 

 

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 rituximab 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 rituximab group (PV Study 1). Patients randomised to the rituximab 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 rituximab compared with mycophenolate mofetil (MMF) in 

patients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment 

with rituximab (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 rituximab 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 drug 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 rituximab-treated PV patients, with 

a ≥ 2% absolute difference in incidence between the rituximab-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 rituximab arm and 

assessed as related. 

 

Table 7 Adverse drugs reactions in rituximab-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 



29  

MedDRA System Organ Class Very Common Common 

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 rituximab 

treatment; three of the four patients experienced serious (life-threatening) IRRs.  Serious IRRs 

occurred at the first (2 patients) or second (1 patient) infusion and resolved with symptomatic 

treatment. 

 

Infections 

In PV Study 1, 14 patients (37%) in the rituximab group experienced treatment-related infections 

compared to 15 patients (42%) in the standard-dose prednisone group. The most common infections 

in the rituximab group were herpes simplex and zoster infections, bronchitis, urinary tract infection, 

fungal infection and conjunctivitis. Three patients (8%) in the rituximab group experienced a total 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 rituximab arm experienced infections.  The most common 

infections in the rituximab group were upper respiratory tract infection, nasopharyngitis, oral 



30  

candidiasis and urinary tract infection.  Six patients (9%) in the rituximab arm experienced serious 

infections. 

 

Laboratory abnormalities 

PV Study 2, in the rituximab 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 rituximab formulation 

is available from clinical trials in humans. The highest intravenous dose of rituximab 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 post-marketing setting five cases of rituximab 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: L01XC02.  

 

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

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

 

Rituximab binds specifically to the transmembrane antigen, CD20, a non-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 internalize 

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 



31  

the surface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 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 rituximab. 

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 rituximab 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 rituximab 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 rituximab. 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 time 

point. 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 rituximab 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 nor 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 rituximab. 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. 

 

Initial treatment, weekly for 8 doses 

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

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

ORR was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a 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 rituximab 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 multicentre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular 



32  

B cell NHL, who had achieved an objective clinical response to a prior course of rituximab, were 

re-treated with 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. Three of the 

patients had received two courses of rituximab 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 rituximab (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 rituximab 375 mg/m2 in combination with CVP (R-CVP). 

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

R-CVP, 159 CVP) received therapy and were analysed for efficacy. The median follow-up 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 rituximab 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. 

 

Table 8 Summary of key results from four phase III randomised studies evaluating 

the benefit of rituximab 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 



33  

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, multicentre, 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 rituximab maintenance therapy 

(n=505) or observation (n=513). The two treatment groups were well balanced with regards to 

baseline characteristics and disease status. Rituximab maintenance treatment consisted of a single 

infusion of rituximab 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 randomisation, maintenance therapy with rituximab 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 rituximab 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 rituximab maintenance therapy in terms of PFS, EFS, TNLT and TNCT (Table 

9). 

 
Table 9 Overview of efficacy results for rituximab maintenance vs. observation at 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 

Rituximab 

N=505 

Observation 

N=513 

Rituximab 

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 



34  

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.  

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

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

 

Rituximab maintenance treatment provided consistent benefit in all predefined subgroups tested: 

gender (male, female), age (< 60 years, ≥ 60 years), FLIPI score (≤1, 2 or ≥ 3), induction therapy (R-

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

CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less pronounced 

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

 

Relapsed/Refractory follicular lymphoma 

 

In a prospective, open label, international, multicentre, 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 rituximab 

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 rituximab maintenance 

therapy (n=167) or observation (n=167). Rituximab maintenance treatment consisted of a single 

infusion of rituximab at 375 mg/m2 body surface area given every 3 months until disease 

progression or for a maximum period of two years. 

 

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 rituximab 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 rituximab 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 rituximab maintenance 

treatment when compared to observation (95% CI; 45%-72%). Kaplan-Meier estimated 

progression-free rates at 12 months were 78% in the rituximab maintenance group vs. 57% in the 



35  

observation group. An analysis of overall survival confirmed the significant benefit of rituximab 

maintenance over observation (p=0.0039 log-rank test). Rituximab maintenance treatment reduced 

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

 

Table 11 Maintenance phase: overview of efficacy results rituximab vs. observation (28 

months median observation time) 

Efficacy Parameter 

Kaplan-Meier Estimate of 

Median Time to Event (months) Risk 

Reduction Observation 

(N = 167) 

Rituximab 

(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 11.6 37.5 < 0.0001 71% 

R-CHOP 22.1 51.9 0.0071 46% 

CR 14.3 52.8 0.0008 64% 

PR 14.3 37.8 < 0.0001 54% 

OS     

CHOP NR NR 0.0348 55% 

R-CHOP NR NR 0.0482 56% 
NR: not reached; a: only applicable to patients achieving a CR 
 

The benefit of rituximab maintenance treatment was confirmed in all subgroups analysed, regardless 

of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) 

(Table 11). Rituximab maintenance treatment significantly prolonged median PFS in 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, rituximab 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 

rituximab 375 mg/m2 plus CHOP (R-CHOP). Rituximab was administered on the first day of the 

treatment cycle. 

 

The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a 

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. 



36  

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 rituximab in 

combination with FC (R-FC). Rituximab 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. 

 

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 rituximab 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) 

CR rates 

72.6% 

16.9% 

85.8% 

36.0% 

<0.0001 

<0.0001 

N/A 

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 

 



37  

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. 

 
Table 13 Treatment of relapsed/refractory chronic lymphocytic leukaemia - overview 

of efficacy results for rituximab plus FC vs. FC alone (25.3 months median 

observation time) 

Efficacy Parameter Kaplan-Meier Estimate of 

Median Time to Event (months) 

(months9(months(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) 

 

 

CR rates 

 

Duration of response * 

Disease free survival (DFS)** 

 

 

Time to new CLL treatment 

58.0% 

 

 

13.0% 

 

27.6 

42.2 

 

 

34.2 

69.9% 

 

 

24.3% 

 

39.6 

39.6 

 

 

NR 

0.0034 

 

 

0.0007 

 

0.0252 

0.8842 

 

 

0.0024 

N/A 

 

 

N/A  

 

31% 

‐6% 

 

 

35% 

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

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

**: only applicable to patients achieving a CR; 

 

Results from other supportive studies using rituximab in combination with other 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 rituximab with any chemotherapy. 

 

Data in approximately 180 patients pre-treated with rituximab have demonstrated clinical 

benefit (including CR) and are supportive for rituximab re-treatment. 

 

Paediatric population 

 

A multicenter, open-label, randomized study of Lymphome Malin B (LMB) chemotherapy 

(corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, 



38  

etoposide and triple drug [methotrexate/cytarabine/ corticosteroid] intrathecal therapy) alone or in 

combination with rituximab 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 rituximab 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 rituximab in combination with LMB chemotherapy. 

 

The two treatment arms, LMB (LMB chemotherapy) and R-LMB (LMB chemotherapy with 

rituximab), were well balanced with regards to baseline characteristics. Patients had a median age of 7 

and 8 years 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 

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 rituximab.   

 

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%)  

 



39  

The primary efficacy analysis showed an EFS benefit of rituximab addition to LMB chemotherapy 

over LMB chemotherapy alone, with an EFS HR 0.32 (90% CI 0.17 - 0.58) from a Cox regression 

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 

rituximab addition to LMB chemotherapy was also shown in the secondary endpoint of OS, with the 

OS HR of 0.36 (95% CI, 0.16 – 0.81). 

 

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

rituximab in all subsets of the paediatric population with follicular lymphoma and chronic 

lymphocytic leukaemia, 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 rituximab 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, multicentre trial (Trial 1). 

 

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one or 

more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according 

to the criteria of the American College of Rheumatology (ACR). Rituximab was administered as two 

IV infusions separated by an interval of 15 days. Patients received 2 x 1000 mg intravenous infusions 

of rituximab 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 rituximab 

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

 

Trials of rituximab in patients with early arthritis (patients without prior methotrexate treatment and 

patients with an inadequate response to methotrexate, but not yet treated with TNF-alpha inhibitors) 

have met their primary endpoints. Rituximab is not indicated for these patients, since the safety data 

about long-term rituximab treatment are insufficient, in particular concerning the risk of 

development of malignancies and PML. 

 

Disease activity outcomes 

Rituximab 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 Rituximab+MTX 

(2 x 1000 mg) 

Trial 1  N= 201 N= 298 

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

 

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

 

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

 



40  

 EULAR Response 

(Good/Moderate) 
44 (22%) 193 (65%)

***
 

 Mean change in DAS ‐0.34 ‐1.83
***

 

† Outcome at 24 weeks 

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

 

Patients treated with rituximab in combination with methotrexate had a significantly 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 rituximab treated patients treated with rituximab 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 rituximab 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 rituximab either as 

rescue between weeks 16-24 or in the extension trial, before week 56. A higher proportion of 

patients receiving the original rituximab/MTX treatment also had no erosive progression over 56 

weeks (Table 16). 

 

Table 16 Radiographic outcomes at 1 year (mITT population) 

 Placebo+MTX Rituximab +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 rituximab 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 rituximab compared to patients treated with methotrexate alone. The 

proportions of rituximab treated patients showing a minimal clinically important difference (MCID) in 

HAQ-DI (defined as an individual total score decrease of >0.22) was also higher than among patients 



41  

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

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

 

Outcome† 
Placebo+MTX 

Rituximab+MTX 

(2 x 1000 mg) 

 

 

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 

 

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 rituximab in combination with methotrexate showed an enhanced 

response compared to patients negative to both. 

 

Efficacy outcomes in rituximab 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. 

 



42  

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

 
 

Long-term efficacy with multiple course therapy 

Treatment with rituximab 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. 

 

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 ADA in clinical 

studies following therapy with rituximab. The emergence of ADA was 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 



43  

 

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

rituximab 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, multicentre, 

non-inferiority trial. 

 

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2 mg/kg/day) 

for 3-6 months or rituximab (375 mg/m2) once weekly for 4 weeks. All patients in the 

cyclophosphamide arm received azathioprine maintenance therapy 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 study treatment. 

 

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

Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off 

glucocorticoid therapy. The pre-specified non-inferiority margin for the treatment difference was 

20%. The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete 

remission (CR) at 6 months (Table 19). 

 

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing 

disease (Table 20). 

 

Table 19 Percentage of adult patients who achieved complete remission at 6 months 

(Intent-to-treat population*) 

 
Rituximab 

(n = 99) 
Cyclophosphamide 

(n = 98) 

Treatment difference 

(Rituximab -

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 

 Rituximab Cyclophosphamide Difference (CI 95%) 

All patients 

Newly diagnosed 

Relapsing 

n=99 

n=48 

n=51 

n=98 

n=48 

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 

 



44  

 

Complete remission at 12 and 18 months 

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

CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine 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 

rituximab group compared with four in the cyclophosphamide group. 

 

Laboratory evaluations 

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

for ADA by 18 months. None of the 99 rituximab-treated patients were ADA positive at screening. 

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

induction of the 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 randomised to receive azathioprine (59 patients) or rituximab (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 rituximab (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 

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 rituximab 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 rituximab 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 rituximab 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 rituximab starting from month 2 and was maintained up to month 28 (Figure 3). 



45  

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 rituximab treated patients from the maintenance therapy clinical trial 

developed ADA. There was no apparent trend or negative impact of the presence of ADA on safety or 

efficacy in the maintenance therapy clinical trial.  

 

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 

rituximab 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 rituximab 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 rituximab infusions on or after Month 6 to maintain 

PVAS remission and control disease activity (including progressive disease or flare) or to achieve first 

remission. 

Survival Time (Months) 

P
er

ce
n

ta
ge

 o
f 

P
at

ie
n

ts
 w

it
h

 F
ir

st
 

M
aj

o
r 

R
el

ap
se

 



46  

 

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 rituximab 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 rituximab (up to 4.5 

yrs [53.8 months]). Patients received up to 375 mg/m2 x 4 of rituximab, approximately every 6 months 

at 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. 

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 the 

assessment time-point. 
αt he efficacy results are exploratory and no formal statistical testing was performed for these endpoints rituximab, 

treatment (375 mg/m2 x 4 infusions) up to Month 6 was identical for all patients. Follow-up treatment post Month 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 

rituximab in paediatric population < 2 years of age in severe, active GPA or MPA. See section 4.2 for 

information on paediatric use. 



47  

 

Clinical experience in pemphigus vulgaris 

 

PV Study 1 (Study ML22196) 

The efficacy and safety of rituximab in combination with short-term, low-dose glucocorticoid 

(prednisone) therapy were evaluated in newly diagnosed patients with moderate to severe pemphigus 

(74 pemphigus vulgaris [PV] and 16 pemphigus foliaceus [PF]) in this randomised, open-label, 

controlled, multicenter study. Patients were between 19 and 79 years of age and had not received prior 

therapies for pemphigus. In the PV population, 5 (13%) patients in the rituximab group and 3 (8%) 

patients in the standard prednisone group had moderate disease and 33 (87%) patients in the rituximab 

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 rituximab and low-dose prednisone or standard-dose prednisone. Patients randomised to 

the rituximab group received an initial intravenous infusion of 1000 mg rituximab 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 rituximab 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 rituximab group who relapsed could receive an additional infusion of rituximab 

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.  

 

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 rituximab and low-dose prednisone over standard-

dose prednisone in achieving CRoff  2 months at month 24 in PV patients (see Table 22).   

Table 22  Percentage of PV patients who achieved complete remission off 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% CI b 

Number of responders      

(response rate [%]) 

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

a p-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 rituximab (Figure 4).  



48  

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

over time 

 

Post-hoc retrospective laboratory evaluation 

A total of 19/34 (56%) patients with PV, who were treated with rituximab, tested positive for ADA 

antibodies by 18 months. The clinical relevance of ADA formation in rituximab-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 rituximab 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).   
One hundred and thirty-five patients were randomized to treatment with rituximab 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 rituximab 

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 rituximab over MMF in combination with a tapering course 

of oral corticosteroids in achieving CR off corticosteroid  16 weeks at Week 52 in PV patients (Table 

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

had established disease (duration of illness  6 months and received prior treatment for PV).  

 



49  

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

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

Population) 
 Rituximab 

(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 rituximab 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 rituximab.  

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

rituximab 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 rituximab compared 

to MMF (6 vs. 44, p<0.0001) and there were fewer patients who had at least one disease flare (8.1% 

vs. 41.3%). 

 

Laboratory evaluations 

By week 52, a total of 20/63 (31.7%) (19 treatment-induced and 1 treatment-enhanced) rituximab -

treated PV patients tested positive for ADA.  There was no apparent negative impact of the presence 

of ADA on safety or efficacy in PV Study 2. 

 

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 rituximab as a single agent or in combination with CHOP therapy (applied 

rituximab 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 rituximab was 22 days (range, 

6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumour lesions 

contributed to some of the variability in CL2 of rituximab 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 

rituximab. This analysis suggests that dose adjustment of rituximab with any of the tested covariates 

is not expected to result in a meaningful reduction in its pharmacokinetic variability. 

 



50  

Rituximab, 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 rituximab, 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 rituximab 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 rituximab when administered as 6 infusions of 375 mg/m2 in 

combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab 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 (3 to 12 years 

vs. 12 to <18 years). After two rituximab IV infusions of 375 mg/m2 in each of the two induction 

cycles (cycle 1 and 2) followed by one rituximab 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 rituximab in paediatric patients with DLBCL/BL/BAL/BLL were similar to 

what has been observed in adult NHL patients. 

 

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 

 

Rituximab 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 rituximab 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 



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 × 500 mg dose and ranged from 298 to 341 μg/mL 

for 2 × 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 × 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 × 500 mg dose and 317 to 370 μg/mL for 2 × 1000 mg dose. Cmax 

following second infusion, was 207 μg/mL for the 2 × 500 mg dose and ranged from 377 to 386 

μg/mL for the 2 × 1000 mg dose. Mean terminal elimination half-life after the second infusion, 

following the second course, was 19 days for 2 × 500 mg dose and ranged from 21 to 22 days for the 

2 × 1000 mg dose. PK 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 × 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. 

 

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 rituximab 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 rituximab 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. 

 



52  

Pemphigus vulgaris 

 

The PK parameters in adult PV patients receiving rituximab 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. 

 

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 chloride  

Tri-sodium citrate dihydrate (E331) 

Polysorbate 80 (E433) 

Water for injections 



53  

 

6.2 Incompatibilities 

 

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

have been observed. 

 

6.3 Shelf life 

 

Unopened vial  

4 years 

 

Diluted product 

The prepared infusion solution of rituximab in 0.9% sodium chloride solution is physically 

and chemically stable for 30 days at 2 °C - 8 °C and subsequently 24 hours at room 

temperature (not more than 30 °C). 

The prepared infusion solution of rituximab in 5% glucose solution is physically and 

chemically stable for 24 hours at 2 °C - 8 °C and subsequently 12 hours at room temperature 

(not more than 30 °C). 

 

From a microbiological point of view, the prepared infusion solution should be used immediately. 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. 

 

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 

 

Blitzima 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. 

 

Blitzima 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 

 

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

 

Aseptically withdraw the necessary amount of Blitzima, 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. 

 

 



54  

7. MARKETING AUTHORISATION HOLDER 

 

Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 

Hungary 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 
 

Blitzima 100 mg concentrate for solution for infusion 

EU/1/17/1205/002 

 

Blitzima 500 mg concentrate for solution for infusion 

EU/1/17/1205/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 13 July 2017 

Date of latest renewal: 

 

10. DATE OF REVISION OF THE TEXT 
 

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

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



55  

 
 

 

 

 

 

 

 

 

 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER 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 

 



56 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer of the biological active substance 

CELLTRION Inc. (Plant II, CLT2), 

20 Academy–ro 51 beon-gil 

Yeonsu-gu, Incheon, 22014, Republic of Korea 

CELLTRION Inc. (Plant I, CLT1), 

23 Academy–ro  

Yeonsu-gu, Incheon, 22014, Republic of Korea 

Name and address of the manufacturers responsible for batch release 

Biotec Services International Ltd. 

Biotec House, Central Park, Western Avenue 

Bridgend Industrial Estate 

Bridgend, CF31 3RT, UK  

Units 2100, 2110, 2010, 2120, 2130 and 2500 

Phase 18, Central Park 

Bridgend Industrial Estate 

Bridgend, CF31 3TY, UK 

Millmount Healthcare Ltd. 

Block 7, City North Business Campus,  

Stamullen, Co. Meath K32 YD60, Ireland 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

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 required pharmacovigilance activities 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 



57  

authorisation and any agreed subsequent updates of the RMP. 

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.  

 Additional risk minimisation measures  

Non-oncology indications: 

The MAH must ensure that all physicians who are expected to prescribe Blitzima are provided with 

the following: 

Product information  

Physician information  

Patient information  

Patient Alert card 

The Physician information about Blitzima 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 Blitzima 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 Blitzima 

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 Blitzima 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 Blitzima 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 

 

Oncology indications: 

The MAH must ensure that all physicians who are expected to prescribe Blitzima are provided with 

the following: 

Product information  

Physician information  



58  

 

The Physician information about Blitzima should contain the following key elements: 

 Information that the product should be administered as IV only to avoid administration route 

errors. 

The Physician information and Patient information must be agreed with the National Competent 

Authorities prior to distribution and Patient Alert Card should be included as part of inner packaging. 

  



59  

 

 

 

 

 

 

 

 

 

 
 
 
 
 
 
 
 
 
 
 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



60  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

  



61  

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 
Blitzima 100 mg concentrate for solution for infusion 

Rituximab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 vial contains 100 mg of rituximab. 

1 mL contains 10 mg of rituximab. 

 

 

3. LIST OF EXCIPIENTS 

 
Excipients: sodium chloride, tri-sodium citrate dihydrate, polysorbate 80, water for injections. 

This medicinal product contains sodium. Read the leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 
Concentrate for solution for infusion 

100 mg / 10 mL 

2 vials 

 

 

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 

 

 



62  

9. SPECIAL STORAGE CONDITIONS 

 
Store in a refrigerator. Keep the container 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 

 
Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 

Hungary 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 
 EU/1/17/1205/002 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

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: 

 

 
 



63  

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Blitzima 100 mg concentrate for solution for infusion 

Rituximab 

Intravenous use 

 

 

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 

 

(10 mg/mL) 

100 mg / 10 mL 

 

 

6. OTHER 

 

  



64  

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 
Blitzima 500 mg concentrate for solution for infusion 

Rituximab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 vial contains 500 mg of rituximab. 

1 mL contains 10 mg of rituximab. 

 

 

3. LIST OF EXCIPIENTS 

 
Excipients: sodium chloride, tri-sodium citrate dihydrate, polysorbate 80, water for injections. 

This medicinal product contains sodium. Read the leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 
Concentrate for solution for infusion 

500 mg / 50 mL 

1 vial 

 

 

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 

 

 



65  

9. SPECIAL STORAGE CONDITIONS 

 
Store in a refrigerator. Keep the container 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 

 
Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 

Hungary 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 
EU/1/17/1205/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

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: 

 

 



66  

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Blitzima 500 mg concentrate for solution for infusion 

Rituximab 

Intravenous use 

 

 

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 

 

(10 mg/mL) 

500 mg / 50 mL 

 

 

6. OTHER 

 

 
 
  



67  

 
PATIENT ALERT CARD TEXT FOR NON-ONCOLOGY INDICATIONS 

 

Blitzima (Rituximab) 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 

Blitzima 

• 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 Blitzima. 

 

Keep this card with you for 2 years after 

your last dose of Blitzima. 

This is because side effects can develop 

several months after you have had 

treatment. 

 

When should I not have Blitzima? 

 

Do not have Blitzima 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 are the signs of getting an infection? 

 

 

What else do I need to know? 

 

Rarely Blitzima 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 Blitzima treatment. 

 

Where can I get more information? 

 

See the Blitzima 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. 



68  

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 

Blitzima treatment. 

 

 



69  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

  



70  

Package leaflet: Information for the patient 
 

Blitzima 100 mg concentrate for solution for infusion 

Blitzima 500 mg concentrate for solution for infusion 
 

rituximab 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

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 Blitzima is and what it is used for 

2. What you need to know before you use Blitzima 

3. How to use Blitzima 

4. Possible side effects 

5. How to store Blitzima 

6. Contents of the pack and other information 

 

 

1. What Blitzima is and what it is used for  

 
What Blitzima is 
Blitzima 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 Blitzima is used for 
Blitzima may be used for the treatment of several different conditions in adults and children. Your 

doctor may prescribe Blitzima 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, Blitzima can be given alone or with other medicines called “chemotherapy”. 

In adult patients where the treatment is working, Blitzima may be continued for 2 years after 

completing the initial treatment. 

In children and adolescents, Blitzima 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. Blitzima in combination with chemotherapy destroys these cells which are gradually 

removed from the body by biological processes. 

 

c) Granulomatosis with polyangiitis or microscopic polyangiitis 

Blitzima 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 



71  

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. 

 

d) Pemphigus vulgaris 

Blitzima 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 Blitzima  

 
Do not take Blitzima 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 granulomatosis with 

polyangiitis, microscopic polyangiitis or pemphigus vulgaris. 

 

Do not have Blitzima if any of the above apply to you. If you are not sure, talk to your doctor, 

pharmacist or nurse before you are given Blitzima. 

 

Warnings and precautions 
Talk to your doctor, pharmacist or nurse before you are given Blitzima if: 

 

• you have ever had or might now have a hepatitis infection. This is because in a few cases, 

Blitzima 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 Blitzima. Your doctor may need to take special care of you during your treatment with 

Blitzima. 

 

If you have 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 Blitzima help to fight infection and you should wait until the infection has passed before you 

are given Blitzima. Also please tell your doctor if you had a lot of infections in the past or suffer 

from severe infections. 

• 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 Blitzima or in 

the months after you receive Blitzima. Your doctor will check if you should have any vaccines 

before you receive Blitzima. 

 

Children and adolescents 
Non-Hodgkin’s lymphoma 

Blitzima 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. 



72  

 

Granulomatosis with polyangiitis or microscopic polyangiitis 

Blitzima 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 Blitzima 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 Blitzima 
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 Blitzima can affect the way some other medicines work. Also some other medicines can affect 

the way Blitzima 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 Blitzima. This is because some people have a fall in 

their blood pressure while they are being given Blitzima. 

• 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 Blitzima. 

 

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 Blitzima can across 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 Blitzima. You must also do this for 12 months after your last treatment with 

Blitzima. 

Do not breast-feed while you are being treated with Blitzima. Also do not breast-feed for 12 months 

after your last treatment with Blitzima. This is because Blitzima may pass into breast milk. 

 

Driving and using machines 
It is not known whether Blitzima has an effect on you being able to drive or use any tools or 

machines. 

 

Blitzima contains sodium 

This medicine contains 52.6 mg sodium (main component of cooking/table salt) in each 10 mL vial 

and 263.2 mg sodium (main component of cooking/table salt) 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. 

 

3. How Blitzima is given  

 
How it is given 
Blitzima 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 Blitzima as a drip (intravenous infusion). 

 

Medicines given before each Blitzima administration 
Before you are given Blitzima, you will be given other medicines (pre-medication) to prevent or 

reduce possible side effects. 

 



73  

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 Blitzima alone 

Blitzima will be given to you once a week for 4 weeks. Repeated treatment courses with 

Blitzima are possible. 

• If you are having Blitzima with chemotherapy 

Blitzima 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 Blitzima 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 Blitzima with chemotherapy.  You will 

receive Blitzima 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 Blitzima in combination with chemotherapy, you will receive Blitzima 

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 Blitzima infusion. Your doctor will decide if 

you should receive concomitant supportive therapy. 

 

c) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis  
Treatment with Blitzima uses four separate infusions given at weekly intervals. Corticosteroids will 

usually be given by injection before the start of Blitzima 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 Blitzima 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 Blitzima (up to 

5 years), depending on how you respond to the medicine. 

 

d) 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 Blitzima 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. 

 

 

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 Blitzima treatment if these reactions are serious. 

 



74  

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 Blitzima. 

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 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 have 

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 

 

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 “lactate dehydrogenase (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 



75  

• hives, increased sweating, night sweats 

• muscle problems – such as tight muscles, joint or muscle pain, back and neck 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 

 

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 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) 



76  

• 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). 

 

c) 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 

 

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 

Blitzima may also cause changes in laboratory tests carried out by your doctor. 

If you are having Blitzima with other medicines, some of the side effects you may get may be due to 

the other medicines. 

 



77  

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 Blitzima 
 

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 and the vial 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 Blitzima contains 
• The active ingredient in Blitzima 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 chloride, tri-sodium citrate dihydrate, polysorbate 80 and 

water for injections. 

 

 
What Blitzima looks like and contents of the pack 
 

Blitzima 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 

 
Marketing Authorisation Holder 
 

Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 

Hungary 

 

Manufacturer 
 

Biotec Services International Ltd. 
Biotec House, Central Park, Western Avenue 
Bridgend Industrial Estate 
Bridgend, CF31 3RT, UK  
 

And 
 
Units 2100, 2110, 2010, 2120, 2130 and 2500 



78  

Phase 18, Central Park 
Bridgend Industrial Estate 
Bridgend, CF31 3TY, UK 

Millmount Healthcare Ltd. 
Block 7, City North Business Campus,  
Stamullen, Co. Meath K32 YD60, Ireland 
 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Mundipharma BV 

Tél/Tel: + 32 15 45 1180 

 

Lietuva 

EGIS PHARMACEUTICALS PLC atstovybė 

Tel: +370 5 231 4658 

България 

EGIS Bulgaria EOOD 

Teл.: + 359 2 987 6040 

Luxembourg/Luxemburg 
Mundipharma BV 

Tél/Tel: + 32 15 45 1180 

 

Česká republika 

EGIS Praha, spol. s r.o 

Tel: +420 227 129 111 

Magyarország 

Egis Gyógyszergyár Zrt. 

Tel.: + 36 1 803 5555 

  

Danmark 

Orion Pharma A/S  

Tlf: + 45 86 14 00 00 

Malta 
Medical Logistics Ltd. 

Tel: +356 2755 9990 

 

Deutschland 

Mundipharma GmbH 

Tel: +49 (0) 69 506029-000 

Nederland 
Mundipharma Pharmaceuticals B.V 

Tel: + 31 33 450 8270 

 

Eesti 

Orion Pharma Eesti OÜ  

Tel: + 372 6 644 550 

 

Norge 
Orion Pharma AS 

Tlf: + 47 40 00 42 10  
 

Ελλάδα 

ΒΙΑΝΕΞ Α.Ε. 

Τηλ: +30 210 8009111 – 120 

 

España 
Kern Pharma, S.L. 

Tel: +34 93 700 2525 

Ö sterreich 
Astro-Pharma GmbH 

Tel: +43 1 97 99 860 

 

Polska 

EGIS Polska Sp. z o.o. 

Tel.: + 48 22 417 9200 

  

France 

Laboratoires Biogaran 

Tél: +33 (0) 800 970 109 

 

Portugal 
PharmaKERN Portugal – Produtos Farmacêuticos, 

Sociedade Unipessoal, Lda. 

Tel: +351 214 200 290 

 

Hrvatska 
Oktal Pharma d.o.o. 

Tel: +385 1 6595 777 

 

România 

Egis Pharmaceuticals PLC Romania 

Tel: + 40 21 412 0017 

 

Ireland 
Mundipharma Pharmaceuticals Limited 

Tel: +353 1 2063800 

 

Slovenija 

OPH Oktal Pharma d.o.o.  

Tel: +386 1 519 29 22 

  

Ísland 
Vistor hf.  

Slovenská republika 

EGIS SLOVAKIA spol. s r.o 



79  

Sími: +354 535 7000 

 

Tel: +421 2 3240 9422 

Italia 
Mundipharma Pharmaceuticals Srl 

Tel: +39 02 31 82 88 1 

 

Suomi/Finland 
Orion Pharma 

Puh/Tel: + 358 10 4261 

 

Κύπρος 

C.A. Papaellinas Ltd 

Τηλ: +357 22741741 

 

Sverige 

Orion Pharma AB 

Tel: + 46 8 623 64 40 

 

Latvija 

EGIS Pharmaceuticals PLC pārstāvniecība Latvijā 

Tel: +371 67613859 

United Kingdom 
NAPP Pharmaceuticals Ltd. 

Tel: +44 1223 424444 

 
This leaflet was last revised in MM/YYYY. 

 
Other sources of information 
 

Detailed information on this medicine is available on the European Medicines Agency web site: 

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

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER 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
	A. LABELLING
	B. PACKAGE LEAFLET