Rituzena

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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 
 
Rituzena 100 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 100 mg of rituximab. 
 
Each mL of concentrate contains 10mg 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. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion.  
Clear, colourless liquid. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rituzena is indicated in adults for the following indications:  
 
Non-Hodgkin’s lymphoma (NHL) 
 
Rituzena is indicated for the treatment of previously untreated patients with stage III-IV follicular 
lymphoma in combination with chemotherapy. 
 
Rituzena monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma 
who are chemo-resistant or are in their second or subsequent relapse after chemotherapy. 
 
Rituzena is indicated for the treatment of patients with CD20 positive diffuse large B cell 
non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, 
prednisolone) chemotherapy. 
 
Chronic lymphocytic leukaemia (CLL) 
 
Rituzena 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 Rituzena or patients refractory to 
previous Rituzena plus chemotherapy. 
 
See section 5.1 for further information. 

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Granulomatosis with polyangiitis and microscopic polyangiitis 
 
Rituzena, in combination with glucocorticoids, is indicated for the induction of remission in adult 
patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic 
polyangiitis (MPA). 
 
4.2 Posology and method of administration 
 
Rituzena should be administered under the close supervision of an experienced healthcare 
professional, and in an environment where full resuscitation facilities are immediately available (see 
section 4.4). 
 
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and 
diphenhydramine, should always be given before each administration of Rituzena. 
 
In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be 
considered if Rituzena is not given in combination with glucocorticoid-containing chemotherapy. 
 
In patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis, 
methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is 
recommended prior to the first infusion of Rituzena (the last dose of methylprednisolone may be 
given on the same day as the first infusion of Rituzena). 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 Rituzena treatment. 
 
Posology 
 
Non-Hodgkin’s lymphoma 
 
Follicular non-Hodgkin's lymphoma 
 
Combination therapy 
The recommended dose of Rituzena 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. 
Rituzena should be administered on day 1 of each chemotherapy cycle, after intravenous 
administration of the glucocorticoid component of the chemotherapy if applicable. 

 
 
Monotherapy 

• Relapsed/refractory follicular lymphoma 
The recommended dose of Rituzena monotherapy used as induction treatment for adult patients with 
stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse 
after chemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once 
weekly for four weeks. 
 
For retreatment with Rituzena monotherapy for patients who have responded to previous treatment 
with Rituzena 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). 
 
Diffuse large B cell non-Hodgkin's lymphoma 
 
Rituzena 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 Rituzena 

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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 Rituzena are recommended. When Rituzena is given in combination with 
chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be 
applied. 
 
Chronic lymphocytic leukaemia 
 
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 Rituzena to decrease the 
rate and severity of acute infusion reactions and/or cytokine release syndrome. 
 
The recommended dosage of Rituzena 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 Rituzena infusion. 
 
Granulomatosis with polyangiitis and microscopic polyangiitis 
 
Patients treated with Rituzena must be given the patient alert card with each infusion. 
 
The recommended dosage of Rituzena for induction of remission therapy of granulomatosis with 
polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an 
intravenous infusion once weekly for 4 weeks (four infusions in total). 
 
Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with 
granulomatosis with polyangiitis or microscopic polyangiitis during and following Rituzena 
treatment, as appropriate. 
 
Special populations 
 
Elderly 
No dose adjustment is required in elderly patients (aged >65 years). 

 
Paediatric population 
The safety and efficacy of Rituzena in children below 18 years has not been established. No data are 
available. 
 
Method of administration 
 
The prepared Rituzena solution should be administered as an intravenous infusion through a 
dedicated line. It should not be administered as an intravenous push or bolus. 
 
Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). 
Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or 
hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma 
should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory 
tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be 
restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest 
X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the 
previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the 
treatment should be seriously considered on a case by case basis. 

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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 Rituzena 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. 
 
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 and microscopic 
polyangiitis 
 
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). 
 
4.4 Special warnings and precautions for use 
 
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, granulomatosis with polyangiitis and 
microscopic polyangiitis 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 

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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 
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 only 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 

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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, 
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 

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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, 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. 
 
Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis 
 
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. Premedication consisting of an analgesic/anti-pyretic 
medicinal product and an anti-histaminic medicinal product, should always be administered before 
each infusion of rituximab. In rheumatoid arthritis premedication with glucocorticoids should also be 
administered before each infusion of rituximab in order to reduce the frequency and severity of IRRs 
(see sections 4.2 and 4.8). 
 
Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the 
post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials 
were mild to moderate in severity. The most common symptoms were allergic reactions like headache, 
pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion 
of patients experiencing any infusion reaction was higher following the first infusion than following 
the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses 
(see section 4.8). The reactions reported were usually reversible with a reduction in rate, or 
interruption, of 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 

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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 for patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to 
those seen for rheumatoid arthritis patients in clinical trials (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 
Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in 
rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis 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. 

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Immunisation 
Physicians should review the patient’s vaccination status and follow 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 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Currently, there are limited data on possible medicinal product 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 or human anti-chimeric antibody (HAMA/HACA) 
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 

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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. 
 
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 
 
Summary of the safety profile (non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia) 
 
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. 

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 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 1. Within each frequency grouping, undesirable effects are presented in 
order of decreasing seriousness. 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). 
 
The ADRs identified only during post-marketing surveillance, and for which a frequency could 
not be estimated, are listed under “not known”. 
 
Table 1  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 

System organ 
class 

Very 
common Common Uncommon Rare Very Rare Not known 

Infections 
and 
infestations 

bacterial 
infection, 
viral 
infections, 
+bronchitis 

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

 serious viral 
infection2 
Pneumocystis 
jirovecii 

PML  

Blood and 
lymphatic 
system 
disorders 

neutropenia, 
leucopenia, 
+febrile 
neutropenia, 
+thrombocyt 
openia 

anaemia, 
+pancytopenia, 
+granulocytopen
ia 

coagulation 
disorders, 
aplastic 
anaemia, 
haemolytic 
anaemia, 
lymphadenop
athy 

 transient 
increase in 
serum IgM 
levels3 

late 
neutropenia3 

Immune 
system 
disorders 

infusion 
related 
reactions4, 
angioedema 

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

infusion-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, 

dysgeusia  peripheral 
neuropathy, 
facial nerve 

cranial 
neuropathy, 
loss of other 

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System organ 
class 

Very 
common Common Uncommon Rare Very Rare Not known 

insomnia, 
vasodilatation, 
dizziness, 
anxiety 

palsy5 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 
disoders4 and 6 

heart failure4 
and 6 

 

Vascular 
disorders 

 hypertension, 
orthostatic 
hypotension, 
hypotension 

  vasculitis 
(predominatel 
y cutaneous), 
leukocytoclast 
ic vasculiti 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 bronchospasm4, 
respiratory 
disease, chest 
pain, dyspnoea, 
increased 
cough, 
rhinitis 

asthma, 
bronchiolitis 
obliterans, 
lung disorder, 
hypoxia 

interstitial 
lung disease7 

respiratory 
failure4 

lung 
infiltration 

Gastrointesti
nal disorders 

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

abdominal 
enlargement 

 gastro-intestin 
al perforation7 

 

Skin and 
Subcutaneous 
tissue 
disorders 

pruritus, 
rash, 
+alopecia 

urticaria, 
sweating, night 
sweats, +skin 
disorder 

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

 

Musculoskele
tal, 
connective 
tissue and 
bone 
disorders 

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

    

Renal and 
urinary 
disorders 

    renal failure4  

General 
disorders and 
administratio
nsite 
conditions 

fever , chills, 
asthenia, 
headache 

tumour pain, 
flushing, 
malaise, 
cold syndrome, 
+fatigue, 
+shivering, 

infusion site 
pain 

   

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System organ 
class 

Very 
common Common Uncommon Rare Very Rare Not known 

+multi-organ 
failure4 

Investigations decreased 
IgG levels 

     

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

 
Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% 
of patients in clinical trials, and were predominantly seen during the first infusion, usually in the 
first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other 
symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, 
fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, 
dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related 
reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional 
reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary 
oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions 
such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, 
myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis 
syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower 
or unknown frequencies. The incidence of infusion-related symptoms decreased substantially 
with subsequent infusions and is <1% of patients by the eighth cycle of rituximab-containing 
treatment. 
 
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 

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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 ¾ 
thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in 
the FC group. 
 
In studies of rituximab in patients with Waldenstrom’s macroglobulinaemia, transient increases 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 

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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 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 Syndrome) and Stevens-Johnson Syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Patient subpopulations - rituximab monotherapy 
Elderly patients (≥ 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). 

 

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Patient subpopulations - rituximab combination therapy 
Elderly patients (≥ 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. 
 
Summary of the safety profile (rheumatoid arthritis) 
 
The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from 
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 
 
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 2 Summary of adverse drug reactions reported in clinical trials or during post 

marketing surveillance occurring in patients with rheumatoid arthritis receiving 
rituximab 

System organ class Very common Common Uncommon Rare Very rare 

Infections and 
infestations 

upper respiratory 
tract infection, 
urinary tract 
infections 

bronchitis, 
sinusitis, 
gastroenteritis, 
tinea pedis 

  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, 

 3infusion related 
reactions 
(generalised 
oedema, 

  

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System organ class Very common Common Uncommon Rare Very rare 

General 
disorders and 
administration 
site conditions 

pyrexia, pruritus, 
urticaria, throat 
irritation, hot 
flush, 
hypotension, 
rhinitis, rigors, 
tachycardia, 
fatigue, 
oropharyngeal 
pain, peripheral 
oedema, 
erythma) 

 bronchospasm, 
wheezing, 
laryngeal 
oedema, 
angioneurotic 
oedema, 
generalised 
pruritis, 
anaphylaxis, 
anaphylactoid 
reaction) 

  

Metabolism and 
nutritional 
Disorders 

 hypercholesterole
mia 

   

Psychiatric 
disorders 

 depression, 
anxiety 

   

Nervous system 
disorders 

headache paraesthesia, 
migraine, 
dizziness, sciatica 

   

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

atrial flutter 

Gastrointestinal 
disorders 

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

   

Skin and 
subcutaneous 
tissue disorders 

 alopecia   toxic epidermal 
necrolysis 
(Lyell’s 
Syndrome), 
Stevens-Johnson 
Syndrome5 

Musculo-
skeletal 
disorders 

 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 

 
Description of selected adverse reactions 

 
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. 

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Infusion-related reactions 
The most frequent ADRs following receipt of rituximab in clinical studies were IRRs. 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 postmarketing 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 
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 

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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. 
 
Summary of the Safety Profile (granulomatosis with polyangiitis and microscopic polyangiitis) 
 
In the clinical trial in granulomatosis with polyangiitis and microscopic polyangitis, 99 patients were 
treated 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 3 were all adverse events which occurred at an incidence of ≥ 5% in the 
rituximab group. 
 
Table 3 Adverse drug reactions occurring at 6-months in ≥ 5% of patients receiving 

rituximab, and at a higher frequency than the comparator group, in the 
pivotal clinical study. 

Body system 
Adverse reaction 

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% 

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Body system 
Adverse reaction 

Rituximab (n=99) 

Respiratory, thoracic and  
mediastinal disorders 

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

Gastrointestinal  
disorders 

Diarrhoea 18% 
Dyspepsia 6% 
Constipation 5% 

Skin and subcutaneous  
tissue disorders 

Acne 7% 
Musculoskeletal and connective  
tissue disorders 

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

General disorders and  
administration site conditions 

Peripheral oedema 16% 
Investigations 

Decreased haemoglobin 6% 
 
Description of selected adverse drug reactions 
 
Infusion related reactions 
IRRs in the GPA and MPA clinical trial 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. 
Ninety nine patients were treated with rituximab and 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. 
 
Infections 
In the 99 rituximab patients, 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%. 
 
Malignancies 
The incidence of malignancy in rituximab treated patients in the granulomatosis with polyangiitis and 
microscopic polyangiitis 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. 

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Cardiovascular adverse reactions 
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 
granulomatosis with polyangiitis and microscopic polyangiitis patients treated with rituximab. At 6 
months, in the active-controlled, randomised, double-blind, multicentre, non-inferiority trial, 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. There was no increased rate in overall infections or serious infections in 
patients with low IgA, IgG or IgM. 
 
Neutropenia 
In the active-controlled, randomised, double-blind, multicentre, non-inferiority trial of rituximab in 
granulomatosis with polyangiitis and microscopic polyangiitis, 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. The effect of multiple rituximab courses on the development of 
neutropenia in granulomatosis with polyangiitis and microscopic polyangiitis patients has not been 
studied in clinical trials. 
 
Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal 
outcome, have been reported very rarely. 
 
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 

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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  
 
Rituzena 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 
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 patients with granulomatosis with polyangiitis or microscopic 
polyangiitis, 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 

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duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with 
autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT. 
Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or 
high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) 
on response to 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 
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 

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results from all four studies are summarised in table 4. 
 
Table 4 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 

mo 

OS rates, 
% 

M39021 CVP, 159 R-CVP, 162 53 
57 
81 

10 
41 

Median TTP: 
14.7 
33.6 

P<0.0001 

53-months 
71.1 
80.9 

p=0.029 

GLSG’00 
CHOP, 205 
R-CHOP, 
223 

18 90 96 
17 
20 

Median TTF: 
2.6 

years 
Not reached 

p < 0.001 

18-months 
90 
95 

p = 0.016 

OSHO‐39 
MCP, 96 
R-MCP, 
105 

47 75 92 
25 
50 

Median PFS: 
28.8 Not 
reached 

p < 0.0001 

48-months 
74 
87 

p = 0.0096 

FL2000 

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

42 85 94 
49 
76 

Median EFS: 36 
Not reached 
p < 0.0001 

42-months 
84 
91 

p = 0.029 
EFS – Event Free Survival 
TTP – Time to progression or death  
PFS – Progression-Free Survival  
TTF – Time to Treatment Failure 
OS rates – survival rates at the time of the analyses 
 
 
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). Rituzena was administered on the first day of the 
treatment cycle. 
 
The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a 
median follow-up duration of approximately 31 months. The two treatment groups were well 
balanced in baseline disease characteristics and disease status. The final analysis confirmed that R-
CHOP treatment was associated with a clinically relevant and statistically significant improvement in 
the duration of event-free survival (the primary efficacy parameter; where events were death, relapse 
or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p = 0.0001). Kaplan 
Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm 
compared to 13 months in the CHOP arm, representing a risk reduction of 41 %. At 24 months, 
estimates for overall survival were 68.2 % in the R-CHOP arm compared to 57.4 % in the CHOP arm. 
A subsequent analysis of the duration of overall survival, carried out with a median follow-up 
duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), 
representing a risk reduction of 32 %. 
 
The analysis of all secondary parameters (response rates, progression-free survival, disease-free 
survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The 
complete response rate after cycle 8 was 76.2 % in the R-CHOP group and 62.4 % in the CHOP 

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group (p=0.0028). The risk of disease progression was reduced by 46 % and the risk of relapse by 
51 %. In all patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2 
microglobulin, LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow 
involvement), the risk ratios for event-free survival and overall survival (R-CHOP compared with 
CHOP) were less than 0.83 and 0.95 respectively. R-CHOP was associated with improvements in 
outcome for both high- and low-risk patients according to age adjusted IPI. 
 
Clinical laboratory findings 
 
Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of 
356 patients evaluated for HACA, 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 5a and Table 5b) and 552 patients 
(276 R-FC, 276 FC) for the relapsed/refractory study (Table 6) 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 5a). 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 5b). 
 
Table 5a 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 
 
Table 5b First-line treatment of chronic lymphocytic leukaemia 
 Hazard ratios of progression-free survival according to Binet stage 

(ITT) - 48.1 months median observation time 
 
 

Number of 
patients 

Hazard ratio 
(95% CI) 

p-value (Wald 
test, not 

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Progression‐free survival (PFS) FC R‐FC adjusted) 

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

CI: Confidence Interval 
 
In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6 
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 6 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) 

 

Risk  
reduction 

FC 
(N = 276) 

R-FC 
(N=276
 

Log-
Rank p 

 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 
 
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. See section 4.2 for information on paediatric use. 
 
Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis 
 
A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis 

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(75%) and microscopic polyangiitis (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 (2mg/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 1000mg 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 prespecified 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 7). 
 
Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing 
disease (Table 8). 

 
Table 7 Percentage of 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 8 Complete remission at 6-months by disease status 
 Rituximab Cyclophosphamide Difference (CI 95%) 
All patients 
Newly 
diagnosed 

 

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 
 
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. 
 
Retreatment with rituximab 
Based upon investigator judgment, 15 patients received a second course of rituximab therapy for 
treatment of relapse of disease activity which occurred between 6 and 18 months after the first 
course of rituximab. The limited data from the present trial preclude any conclusions regarding the 

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efficacy of subsequent courses of rituximab in patients with granulomatosis with polyangiitis and 
microscopic polyangiitis. 
 
Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses 
(i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with 
reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with 
rituximab has been achieved, continued immunosuppressive therapy may be considered to prevent 
relapse. The efficacy and safety of rituximab in maintenance therapy has not been established. 

 
Laboratory evaluations 
 
A total of 23/99 (23%) rituximab-treated patients in the trial tested positive for HACA by 18 months. 
None of the 99 rituximab-treated patients were HACA positive at screening. The clinical relevance of 
HACA formation in rituximab-treated patients is unclear. 
 
5.2 Pharmacokinetic properties 
 
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. 
 
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. 
 
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). 
 

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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 
L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic 
clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis 
revealed that BSA and gender were the most significant covariates to explain inter-individual 
variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume 
of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic 
differences are not considered to be clinically relevant and dose adjustment is not required. No 
pharmacokinetic data are available in patients with hepatic or renal impairment. 
 
The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg 
and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were 
dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first 
infusion ranged from 157 to 171 µg/mL for 2 x 500 mg dose and ranged from 298 to 341 µg/mL for 2 
x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 µg/mL for the2 x 
500 mg dose and ranged from 355 to 404 µg/mL for the 2 x 1000 mg dose. Mean terminal elimination 
half-life ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days for the 2 x 1000 
mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared to the first 
infusion for both doses. 
 
The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg 
upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was 
170 to 175 µg/mL for 2 x 500 mg dose and 317 to 370 µg/mL for 2 x 1000 mg dose. Cmax following 
second infusion, was 207 µg/mL for the 2 x 500 mg dose and ranged from 377 to 386 µg/mL for the 2 
x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second 
course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose. 
PK parameters for rituximab were comparable over the two treatment courses. 

 
The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following the 
same dosage regimen (2 x 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serum 
concentration of 369 µg/mL and a mean terminal half-life of 19.2 days. 
 
Granulomatosis with polyangiitis and microscopic polyangiitis 
 
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. The PK parameters of rituximab in these 
patients appear similar to what has been observed in rheumatoid arthritis patients. 
 
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. 
 

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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 
Polysorbate 80  
Water for injections 
 
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  
3 years 
 
Diluted product 
The prepared infusion solution of rituximab 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 
 
Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10 mL. Pack of 2 
vials. 
 
6.6 Special precautions for disposal and other handling 
 
Rituzena is provided in sterile, preservative-free, non-pyrogenic, single use vials. 
 
Aseptically withdraw the necessary amount of Rituzena, and dilute to a calculated concentration of 
1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride9 
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 

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solutions. Since the medicinal product does not contain any anti-microbial preservative or 
bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be 
inspected visually for particulate matter and discolouration prior to administration. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Celltrion Healthcare Hungary Kft.  
1062 Budapest 
Váci út 1-3. WestEnd Office Building B torony 
Hungary 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1206/002 
 
 
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/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 
 
Rituzena 500 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 500 mg of rituximab. 
 
Each mL of concentrate contains 10mg 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. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion.  
Clear, colourless liquid. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rituzena is indicated in adults for the following indications:  
 
Non-Hodgkin’s lymphoma (NHL) 
 
Rituzena is indicated for the treatment of previously untreated patients with stage III-IV follicular 
lymphoma in combination with chemotherapy. 
 
Rituzena monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma 
who are chemo-resistant or are in their second or subsequent relapse after chemotherapy. 
 
Rituzena is indicated for the treatment of patients with CD20 positive diffuse large B cell 
non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, 
prednisolone) chemotherapy. 
 
Chronic lymphocytic leukaemia (CLL) 
 
Rituzena 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 Rituzena or patients refractory to 
previous Rituzena plus chemotherapy. 
 
See section 5.1 for further information. 

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Granulomatosis with polyangiitis and microscopic polyangiitis 
 
Rituzena, in combination with glucocorticoids, is indicated for the induction of remission in adult 
patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic 
polyangiitis (MPA). 
 
4.2 Posology and method of administration 
 
Rituzena should be administered under the close supervision of an experienced healthcare 
professional, and in an environment where full resuscitation facilities are immediately available (see 
section 4.4). 
 
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and 
diphenhydramine, should always be given before each administration of Rituzena. 
 
In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be 
considered if Rituzena is not given in combination with glucocorticoid-containing chemotherapy. 
 
In patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis, 
methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is 
recommended prior to the first infusion of Rituzena (the last dose of methylprednisolone may be 
given on the same day as the first infusion of Rituzena). 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 Rituzena treatment. 
 
Posology 
 
Non-Hodgkin’s lymphoma 
 
Follicular non-Hodgkin's lymphoma 
 
Combination therapy 
The recommended dose of Rituzena 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. 
Rituzena should be administered on day 1 of each chemotherapy cycle, after intravenous 
administration of the glucocorticoid component of the chemotherapy if applicable. 

 
 
Monotherapy 

• Relapsed/refractory follicular lymphoma 
The recommended dose of Rituzena monotherapy used as induction treatment for adult patients with 
stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse 
after chemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once 
weekly for four weeks. 
 
For retreatment with Rituzena monotherapy for patients who have responded to previous treatment 
with Rituzena 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). 
 
Diffuse large B cell non-Hodgkin's lymphoma 
 
Rituzena 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 Rituzena 

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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 Rituzena are recommended. When Rituzena is given in combination with 
chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be 
applied. 
 
Chronic lymphocytic leukaemia 
 
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 Rituzena to decrease the 
rate and severity of acute infusion reactions and/or cytokine release syndrome. 
 
The recommended dosage of Rituzena 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 Rituzena infusion. 
 
Granulomatosis with polyangiitis and microscopic polyangiitis 
 
Patients treated with Rituzena must be given the patient alert card with each infusion. 
 
The recommended dosage of Rituzena for induction of remission therapy of granulomatosis with 
polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an 
intravenous infusion once weekly for 4 weeks (four infusions in total). 
 
Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with 
granulomatosis with polyangiitis or microscopic polyangiitis during and following Rituzena 
treatment, as appropriate. 
 
Special populations 
 
Elderly 
No dose adjustment is required in elderly patients (aged >65 years). 

 
Paediatric population 
The safety and efficacy of Rituzena in children below 18 years has not been established. No data are 
available. 
 
Method of administration 
 
The prepared Rituzena solution should be administered as an intravenous infusion through a 
dedicated line. It should not be administered as an intravenous push or bolus. 
 
Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). 
Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or 
hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma 
should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory 
tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be 
restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest 
X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the 
previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the 
treatment should be seriously considered on a case by case basis. 

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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 Rituzena 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. 
 
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 and microscopic 
polyangiitis 
 
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). 
 
4.4 Special warnings and precautions for use 
 
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, granulomatosis with polyangiitis and 
microscopic polyangiitis 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 

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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 
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 only 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 

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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, 
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 

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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, 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. 
 
Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis 
 
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. Premedication consisting of an analgesic/anti-pyretic 
medicinal product and an anti-histaminic medicinal product, should always be administered before 
each infusion of rituximab. In rheumatoid arthritis premedication with glucocorticoids should also be 
administered before each infusion of rituximab in order to reduce the frequency and severity of IRRs 
(see sections 4.2 and 4.8). 
 
Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the 
post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials 
were mild to moderate in severity. The most common symptoms were allergic reactions like headache, 
pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion 
of patients experiencing any infusion reaction was higher following the first infusion than following 
the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses 
(see section 4.8). The reactions reported were usually reversible with a reduction in rate, or 
interruption, of 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 

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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 for patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to 
those seen for rheumatoid arthritis patients in clinical trials (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 
Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in 
rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis 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. 

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Immunisation 
Physicians should review the patient’s vaccination status and follow 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 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Currently, there are limited data on possible medicinal product 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 or human anti-chimeric antibody (HAMA/HACA) 
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 

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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. 
 
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 
 
Summary of the safety profile (non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia) 
 
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. 

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 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 1. Within each frequency grouping, undesirable effects are presented in 
order of decreasing seriousness. 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). 
 
The ADRs identified only during post-marketing surveillance, and for which a frequency could 
not be estimated, are listed under “not known”. 
 
Table 1  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 

System organ 
class 

Very 
common Common Uncommon Rare Very Rare Not known 

Infections 
and 
infestations 

bacterial 
infection, 
viral 
infections, 
+bronchitis 

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

 serious viral 
infection2 
Pneumocystis 
jirovecii 

PML  

Blood and 
lymphatic 
system 
disorders 

neutropenia, 
leucopenia, 
+febrile 
neutropenia, 
+thrombocyt 
openia 

anaemia, 
+pancytopenia, 
+granulocytopen
ia 

coagulation 
disorders, 
aplastic 
anaemia, 
haemolytic 
anaemia, 
lymphadenop
athy 

 transient 
increase in 
serum IgM 
levels3 

late 
neutropenia3 

Immune 
system 
disorders 

infusion 
related 
reactions4, 
angioedema 

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

infusion-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, 

dysgeusia  peripheral 
neuropathy, 
facial nerve 

cranial 
neuropathy, 
loss of other 

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System organ 
class 

Very 
common Common Uncommon Rare Very Rare Not known 

insomnia, 
vasodilatation, 
dizziness, 
anxiety 

palsy5 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 
disoders4 and 6 

heart failure4 
and 6 

 

Vascular 
disorders 

 hypertension, 
orthostatic 
hypotension, 
hypotension 

  vasculitis 
(predominatel 
y cutaneous), 
leukocytoclast 
ic vasculiti 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 bronchospasm4, 
respiratory 
disease, chest 
pain, dyspnoea, 
increased 
cough, 
rhinitis 

asthma, 
bronchiolitis 
obliterans, 
lung disorder, 
hypoxia 

interstitial 
lung disease7 

respiratory 
failure4 

lung 
infiltration 

Gastrointesti
nal disorders 

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

abdominal 
enlargement 

 gastro-intestin 
al perforation7 

 

Skin and 
Subcutaneous 
tissue 
disorders 

pruritus, 
rash, 
+alopecia 

urticaria, 
sweating, night 
sweats, +skin 
disorder 

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

 

Musculoskele
tal, 
connective 
tissue and 
bone 
disorders 

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

    

Renal and 
urinary 
disorders 

    renal failure4  

General 
disorders and 
administratio
nsite 
conditions 

fever , chills, 
asthenia, 
headache 

tumour pain, 
flushing, 
malaise, 
cold syndrome, 
+fatigue, 
+shivering, 

infusion site 
pain 

   

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System organ 
class 

Very 
common Common Uncommon Rare Very Rare Not known 

+multi-organ 
failure4 

Investigations decreased 
IgG levels 

     

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

 
Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% 
of patients in clinical trials, and were predominantly seen during the first infusion, usually in the 
first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other 
symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, 
fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, 
dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related 
reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional 
reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary 
oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions 
such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, 
myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis 
syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower 
or unknown frequencies. The incidence of infusion-related symptoms decreased substantially 
with subsequent infusions and is <1% of patients by the eighth cycle of rituximab-containing 
treatment. 
 
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 

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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 ¾ 
thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in 
the FC group. 
 
In studies of rituximab in patients with Waldenstrom’s macroglobulinaemia, transient increases 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 

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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 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 Syndrome) and Stevens-Johnson Syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Patient subpopulations - rituximab monotherapy 
Elderly patients (≥ 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). 

 

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Patient subpopulations - rituximab combination therapy 
Elderly patients (≥ 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. 
 
Summary of the safety profile (rheumatoid arthritis) 
 
The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from 
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 
 
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 2 Summary of adverse drug reactions reported in clinical trials or during post 

marketing surveillance occurring in patients with rheumatoid arthritis receiving 
rituximab 

System organ class Very common Common Uncommon Rare Very rare 

Infections and 
infestations 

upper respiratory 
tract infection, 
urinary tract 
infections 

bronchitis, 
sinusitis, 
gastroenteritis, 
tinea pedis 

  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, 

 3infusion related 
reactions 
(generalised 
oedema, 

  

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System organ class Very common Common Uncommon Rare Very rare 

General 
disorders and 
administration 
site conditions 

pyrexia, pruritus, 
urticaria, throat 
irritation, hot 
flush, 
hypotension, 
rhinitis, rigors, 
tachycardia, 
fatigue, 
oropharyngeal 
pain, peripheral 
oedema, 
erythma) 

 bronchospasm, 
wheezing, 
laryngeal 
oedema, 
angioneurotic 
oedema, 
generalised 
pruritis, 
anaphylaxis, 
anaphylactoid 
reaction) 

  

Metabolism and 
nutritional 
Disorders 

 hypercholesterole
mia 

   

Psychiatric 
disorders 

 depression, 
anxiety 

   

Nervous system 
disorders 

headache paraesthesia, 
migraine, 
dizziness, sciatica 

   

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

atrial flutter 

Gastrointestinal 
disorders 

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

   

Skin and 
subcutaneous 
tissue disorders 

 alopecia   toxic epidermal 
necrolysis 
(Lyell’s 
Syndrome), 
Stevens-Johnson 
Syndrome5 

Musculo-
skeletal 
disorders 

 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 

 
Description of selected adverse reactions 

 
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. 

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Infusion-related reactions 
The most frequent ADRs following receipt of rituximab in clinical studies were IRRs. 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 postmarketing 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 
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 

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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. 
 
Summary of the Safety Profile (granulomatosis with polyangiitis and microscopic polyangiitis) 
 
In the clinical trial in granulomatosis with polyangiitis and microscopic polyangitis, 99 patients were 
treated 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 3 were all adverse events which occurred at an incidence of ≥ 5% in the 
rituximab group. 
 
Table 3 Adverse drug reactions occurring at 6-months in ≥ 5% of patients receiving 

rituximab, and at a higher frequency than the comparator group, in the 
pivotal clinical study. 

Body system 
Adverse reaction 

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% 

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Body system 
Adverse reaction 

Rituximab (n=99) 

Respiratory, thoracic and  
mediastinal disorders 

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

Gastrointestinal  
disorders 

Diarrhoea 18% 
Dyspepsia 6% 
Constipation 5% 

Skin and subcutaneous  
tissue disorders 

Acne 7% 
Musculoskeletal and connective  
tissue disorders 

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

General disorders and  
administration site conditions 

Peripheral oedema 16% 
Investigations 

Decreased haemoglobin 6% 
 
Description of selected adverse drug reactions 
 
Infusion related reactions 
IRRs in the GPA and MPA clinical trial 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. 
Ninety nine patients were treated with rituximab and 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. 
 
Infections 
In the 99 rituximab patients, 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%. 
 
Malignancies 
The incidence of malignancy in rituximab treated patients in the granulomatosis with polyangiitis and 
microscopic polyangiitis 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. 

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Cardiovascular adverse reactions 
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 
granulomatosis with polyangiitis and microscopic polyangiitis patients treated with rituximab. At 6 
months, in the active-controlled, randomised, double-blind, multicentre, non-inferiority trial, 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. There was no increased rate in overall infections or serious infections in 
patients with low IgA, IgG or IgM. 
 
Neutropenia 
In the active-controlled, randomised, double-blind, multicentre, non-inferiority trial of rituximab in 
granulomatosis with polyangiitis and microscopic polyangiitis, 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. The effect of multiple rituximab courses on the development of 
neutropenia in granulomatosis with polyangiitis and microscopic polyangiitis patients has not been 
studied in clinical trials. 
 
Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal 
outcome, have been reported very rarely. 
 
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 

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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  
 
Rituzena 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 
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 patients with granulomatosis with polyangiitis or microscopic 
polyangiitis, 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 

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duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with 
autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT. 
Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or 
high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) 
on response to 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 
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 

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results from all four studies are summarised in table 4. 
 
Table 4 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 

mo 

OS rates, 
% 

M39021 CVP, 159 R-CVP, 162 53 
57 
81 

10 
41 

Median TTP: 
14.7 
33.6 

P<0.0001 

53-months 
71.1 
80.9 

p=0.029 

GLSG’00 
CHOP, 205 
R-CHOP, 
223 

18 90 96 
17 
20 

Median TTF: 
2.6 

years 
Not reached 

p < 0.001 

18-months 
90 
95 

p = 0.016 

OSHO‐39 
MCP, 96 
R-MCP, 
105 

47 75 92 
25 
50 

Median PFS: 
28.8 Not 
reached 

p < 0.0001 

48-months 
74 
87 

p = 0.0096 

FL2000 

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

42 85 94 
49 
76 

Median EFS: 36 
Not reached 
p < 0.0001 

42-months 
84 
91 

p = 0.029 
EFS – Event Free Survival 
TTP – Time to progression or death  
PFS – Progression-Free Survival  
TTF – Time to Treatment Failure 
OS rates – survival rates at the time of the analyses 
 
 
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). Rituzena was administered on the first day of the 
treatment cycle. 
 
The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a 
median follow-up duration of approximately 31 months. The two treatment groups were well 
balanced in baseline disease characteristics and disease status. The final analysis confirmed that R-
CHOP treatment was associated with a clinically relevant and statistically significant improvement in 
the duration of event-free survival (the primary efficacy parameter; where events were death, relapse 
or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p = 0.0001). Kaplan 
Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm 
compared to 13 months in the CHOP arm, representing a risk reduction of 41 %. At 24 months, 
estimates for overall survival were 68.2 % in the R-CHOP arm compared to 57.4 % in the CHOP arm. 
A subsequent analysis of the duration of overall survival, carried out with a median follow-up 
duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), 
representing a risk reduction of 32 %. 
 
The analysis of all secondary parameters (response rates, progression-free survival, disease-free 
survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The 
complete response rate after cycle 8 was 76.2 % in the R-CHOP group and 62.4 % in the CHOP 

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group (p=0.0028). The risk of disease progression was reduced by 46 % and the risk of relapse by 
51 %. In all patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2 
microglobulin, LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow 
involvement), the risk ratios for event-free survival and overall survival (R-CHOP compared with 
CHOP) were less than 0.83 and 0.95 respectively. R-CHOP was associated with improvements in 
outcome for both high- and low-risk patients according to age adjusted IPI. 
 
Clinical laboratory findings 
 
Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of 
356 patients evaluated for HACA, 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 5a and Table 5b) and 552 patients 
(276 R-FC, 276 FC) for the relapsed/refractory study (Table 6) 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 5a). 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 5b). 
 
Table 5a 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 
 
Table 5b First-line treatment of chronic lymphocytic leukaemia 
 Hazard ratios of progression-free survival according to Binet stage 

(ITT) - 48.1 months median observation time 
 
 

Number of 
patients 

Hazard ratio 
(95% CI) 

p-value (Wald 
test, not 

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Progression‐free survival (PFS) FC R‐FC adjusted) 

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

CI: Confidence Interval 
 
In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6 
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 6 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) 

 

Risk  
reduction 

FC 
(N = 276) 

R-FC 
(N=276
 

Log-
Rank p 

 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 
 
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. See section 4.2 for information on paediatric use. 
 
Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis 
 
A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis 

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(75%) and microscopic polyangiitis (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 (2mg/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 1000mg 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 prespecified 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 7). 
 
Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing 
disease (Table 8). 

 
Table 7 Percentage of 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 8 Complete remission at 6-months by disease status 
 Rituximab Cyclophosphamide Difference (CI 95%) 
All patients 
Newly 
diagnosed 

 

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 
 
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. 
 
Retreatment with rituximab 
Based upon investigator judgment, 15 patients received a second course of rituximab therapy for 
treatment of relapse of disease activity which occurred between 6 and 18 months after the first 
course of rituximab. The limited data from the present trial preclude any conclusions regarding the 

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efficacy of subsequent courses of rituximab in patients with granulomatosis with polyangiitis and 
microscopic polyangiitis. 
 
Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses 
(i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with 
reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with 
rituximab has been achieved, continued immunosuppressive therapy may be considered to prevent 
relapse. The efficacy and safety of rituximab in maintenance therapy has not been established. 

 
Laboratory evaluations 
 
A total of 23/99 (23%) rituximab-treated patients in the trial tested positive for HACA by 18 months. 
None of the 99 rituximab-treated patients were HACA positive at screening. The clinical relevance of 
HACA formation in rituximab-treated patients is unclear. 
 
5.2 Pharmacokinetic properties 
 
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. 
 
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. 
 
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). 
 

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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 
L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic 
clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis 
revealed that BSA and gender were the most significant covariates to explain inter-individual 
variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume 
of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic 
differences are not considered to be clinically relevant and dose adjustment is not required. No 
pharmacokinetic data are available in patients with hepatic or renal impairment. 
 
The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg 
and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were 
dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first 
infusion ranged from 157 to 171 µg/mL for 2 x 500 mg dose and ranged from 298 to 341 µg/mL for 2 
x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 µg/mL for the2 x 
500 mg dose and ranged from 355 to 404 µg/mL for the 2 x 1000 mg dose. Mean terminal elimination 
half-life ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days for the 2 x 1000 
mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared to the first 
infusion for both doses. 
 
The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg 
upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was 
170 to 175 µg/mL for 2 x 500 mg dose and 317 to 370 µg/mL for 2 x 1000 mg dose. Cmax following 
second infusion, was 207 µg/mL for the 2 x 500 mg dose and ranged from 377 to 386 µg/mL for the 2 
x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second 
course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose. 
PK parameters for rituximab were comparable over the two treatment courses. 

 
The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following the 
same dosage regimen (2 x 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serum 
concentration of 369 µg/mL and a mean terminal half-life of 19.2 days. 
 
Granulomatosis with polyangiitis and microscopic polyangiitis 
 
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. The PK parameters of rituximab in these 
patients appear similar to what has been observed in rheumatoid arthritis patients. 
 
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. 
 

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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 
Polysorbate 80  
Water for injections 
 
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 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 
 
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 
 
Rituzena is provided in sterile, preservative-free, non-pyrogenic, single use vials. 
 
Aseptically withdraw the necessary amount of Rituzena, and dilute to a calculated concentration of 
1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride9 
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 

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solutions. Since the medicinal product does not contain any anti-microbial preservative or 
bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be 
inspected visually for particulate matter and discolouration prior to administration. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Celltrion Healthcare Hungary Kft.  
1062 Budapest 
Váci út 1-3. WestEnd Office Building B torony 
Hungary 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1206/001 
 
 
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/ 
  

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64  

 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 

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 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., 
20 Academy–ro 51 beon-gil 
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 periodic safety update reports 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 MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

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• 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 Rituzena are provided with 
the following: 
Product information 
Physician information 
Patient information  
Patient Alert card 

 
The Physician information about Rituzena 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 Rituzena 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 
Rituzena 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 Rituzena 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 Rituzena 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 Rituzena are 
provided with the following: 
Product information  
Physician information  
 
The Physician information about Rituzena 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 

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part of inner packaging. 
  

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  

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A. LABELLING 
  

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rituzena 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. 
 
 
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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 

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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/1/17/1206/002 
 
 
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: 
  

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rituzena 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rituzena 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. 
 
 
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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Keep the container in the outer carton, in order to protect from light. 

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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/1/17/1206/001 
 
 
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: 
  

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rituzena 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 
 
 
 
 
  

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PATIENT ALERT CARD TEXT FOR NON-ONCOLOGY INDICATIONS 
 

Rituzena 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 

Rituzena 
• 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 Rituzena. 

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

 
When should I not have Rituzena? 

 
Do not have Rituzena 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? 

 
Look out for the following possible 
signs of infection: 

 
What else do I need to know? 

 
Rarely Rituzena 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 Rituzena treatment. 

 
Where can I get more information? 

 
See the Rituzena 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. 

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• 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 

Rituzena treatment. 
 
 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the patient 
 

Rituzena 100 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 Rituzena is and what it is used for 
2. What you need to know before you use Rituzena 
3. How to use Rituzena 
4. Possible side effects 
5. How to store Rituzena 
6. Contents of the pack and other information 

 
 
1. What Rituzena is and what it is used for  
 
What Rituzena is 
Rituzena contains the active substance “rituximab”. This is a type of protein called a “monoclonal 
antibody”. It is designed to stick to a type of white blood cell called “B-Lymphocyte”. When 
sticking to the surface of this cell, rituximab causes the cell to die. 
 
What Rituzena is used for 
Rituzena may be used for the treatment of several different conditions in adults. Your doctor may 
prescribe Rituzena for the treatment of: 
 
a) Non-Hodgkin’s Lymphoma 
This is a disease of the lymph tissue (part of the immune system) that affects B-Lymphocytes. 
Rituzena can be given alone or with other medicines called “chemotherapy”. 
 
b) Chronic lymphocytic leukaemia 
Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL affects 
B-lymphocytes, which originate in the bone marrow and develop in the lymph nodes. Patients with 
CLL have too many abnormal lymphocytes, which accumulate mainly in the bone marrow and blood. 
The spread of these abnormal B-lymphocytes is the cause of symptoms you may have. Rituzena in 
combination with chemotherapy destroys these cells. 
 
c) Granulomatosis with polyangiitis or microscopic polyangiitis 
Rituzena is used for inducing remission in granulomatosis with polyangiitis (formerly called 
Wegener’s granulomatosis) or microscopic polyangiitis, taken in combination with corticosteroids. 
Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the 
blood vessels which mainly affects the lungs and kidneys, but may affect other organs as well. 
B-lymphocytes are involved in the cause of these conditions. 
 
 
2. What you need to know before you use Rituzena  

 

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

Rituzena 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 Rituzena. Your doctor may need to take special care during your treatment with 
Rituzena. 
 
If you have granulomatosis with polyangiitis or microscopic polyangiitis 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 Rituzena help to fight infection and you should wait until the infection has passed before you 
are given Rituzena. Also please tell your doctor if you have 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 for travel 
to other countries. Some vaccines should not be given at the same time as Rituzena or in the 
months after you receive Rituzena. Your doctor will check if you should have any vaccines 
before you receive Rituzena. 

 
Children and adolescents 
Talk to your doctor, pharmacist or nurse before you are given this medicine if you, or your child, 
are under 18 years of age. This is because there is not much information about the use of Rituzena 
in children and young people. 

 
Other medicines and Rituzena 
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 Rituzena can affect the way some other medicines work. Also some other medicines can 
affect the way Rituzena 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 Rituzena. This is because some people have a fall in 
their blood pressure while they are being given Rituzena. 

• 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 Rituzena. 
 
Pregnancy and breast-feeding 

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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 Rituzena can transfer 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 Rituzena. You must also do this for 12 months after your last treatment with 
Rituzena. 
Do not breast-feed while you are being treated with Rituzena. Also do not breast-feed for 12 months 
after your last treatment with Rituzena. This is because Rituzena may pass into breast milk. 
 
Driving and using machines 
It is not known whether Rituzena has an effect on you being able to drive or use any tools or 
machines. 
 
 
3. How Rituzena is given  
 
How it is given 
Rituzena 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 Rituzena as a drip (intravenous infusion). 
 
Medicines given before each Rituzena administration 
Before you are given Rituzena, you will be given other medicines (pre-medication) to prevent or 
reduce possible side effects. 
 
How much and how often you will receive your treatment 
 
a) If you are being treated for non-Hodgkin’s Lymphoma 
• If you are having Rituzena alone 

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

• If you are having Rituzena with chemotherapy 
Rituzena will be given to you on the same day as your chemotherapy. This is usually given 

every 3 weeks up to 8 times. 
 
b) If you are being treated for chronic lymphocytic leukaemia 
When you are treated with Rituzena in combination with chemotherapy, you will receive Rituzena 
every 28 days until you have received 6 doses. The chemotherapy should be given after the Rituzena 
infusion. Your doctor will decide if you should receive other treatment at the same time. 
 
 
c) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis  
Treatment with Rituzena uses four separate infusions given at weekly intervals. A corticosteroid 
medicine will usually be given by injection before the start of Rituzena treatment. Corticosteroid 
medicine given by mouth may be started at any time by your doctor to treat your condition. 
 
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. 
 

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Infusion reactions 
During or within the first 2 hours of the first infusion you may develop fever, chills and shivering. 
Less frequently, some patients may get pain at the infusion site, blisters, itching, sickness, tiredness, 
headache, breathing difficulties, 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 
infusion reactions might get worse. Tell the person giving you the infusion immediately if you 
develop 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 Rituzena treatment if these reactions are 
serious. 
 
Infections 
Tell your doctor immediately if you get signs of an infection including: 
 
• fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell 
• memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare, 

serious brain infection, which has been fatal (progressive multifocal leukoencephalopathy or 
PML). 

You might get infections more easily during your treatment with Rituzena. 
These are often colds, but there have been cases of pneumonia or urinary infections. These are 
listed below under “Other side effects”. 
 
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 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 sometimes with fever, or low number of 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 and uneven or fast heart rate 

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• high or low blood pressure (low blood pressure especially when standing upright) 
• tightening of the muscles in the airways which causes wheezing (bronchospasm), 

inflammation, irritation in the lungs, throat or sinuses, being short of breath, runny 
nose 

• being sick (vomiting), diarrhoea, pain in the stomach, irritation or ulcers in the throat 
and mouth, problems swallowing, constipation, indigestion 

• eating disorders: not eating enough, leading to weight loss 
• hives, increased sweating, night sweats 
• muscle problems – such as tight muscles, joint or muscle pain, back and neck pain 
• 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 

 
b) If you 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) 

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• 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 
• blocked 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 
 
Rituzena may also cause changes in laboratory tests carried out by your doctor. 
 
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 Rituzena 
 
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 Rituzena contains 

• The active ingredient in Rituzena is called rituximab. The vial contains 100 mg of 
rituximab. Each mL of concentrate contains 10 mg of rituximab.  

• The other ingredients are sodium chloride, tri-sodium citrate dihydrate, polysorbate 80 and 
water for injections. 

 
What Rituzena looks like and contents of the pack 
 

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Rituzena is a clear, colourless solution, supplied as a concentrate for solution for infusion in a glass 
vial. Pack of 2 vials. 
 
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 
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 CVA 
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 CVA 
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 

Österreich 
Astro-Pharma GmbH 
Tel: +43 1 97 99 860 

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España 
Kern Pharma, S.L. 
Tel: +34 93 700 2525 

 
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.  
Sími: +354 535 7000 
 

Slovenská republika 
EGIS SLOVAKIA spol. s r.o 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Package leaflet: Information for the patient 
 

Rituzena 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: 
7. What Rituzena is and what it is used for 
8. What you need to know before you use Rituzena 
9. How to use Rituzena 
10. Possible side effects 
11. How to store Rituzena 
12. Contents of the pack and other information 

 
 
7. What Rituzena is and what it is used for  
 
What Rituzena is 
Rituzena contains the active substance “rituximab”. This is a type of protein called a “monoclonal 
antibody”. It is designed to stick to a type of white blood cell called “B-Lymphocyte”. When 
sticking to the surface of this cell, rituximab causes the cell to die. 
 
What Rituzena is used for 
Rituzena may be used for the treatment of several different conditions in adults. Your doctor may 
prescribe Rituzena for the treatment of: 
 
d) Non-Hodgkin’s Lymphoma 
This is a disease of the lymph tissue (part of the immune system) that affects B-Lymphocytes. 
Rituzena can be given alone or with other medicines called “chemotherapy”. 
 
e) Chronic lymphocytic leukaemia 
Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL affects 
B-lymphocytes, which originate in the bone marrow and develop in the lymph nodes. Patients with 
CLL have too many abnormal lymphocytes, which accumulate mainly in the bone marrow and blood. 
The spread of these abnormal B-lymphocytes is the cause of symptoms you may have. Rituzena in 
combination with chemotherapy destroys these cells. 
 
f) Granulomatosis with polyangiitis or microscopic polyangiitis 
Rituzena is used for inducing remission in granulomatosis with polyangiitis (formerly called 
Wegener’s granulomatosis) or microscopic polyangiitis, taken in combination with corticosteroids. 
Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the 
blood vessels which mainly affects the lungs and kidneys, but may affect other organs as well. 
B-lymphocytes are involved in the cause of these conditions. 

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8. What you need to know before you use Rituzena  

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

Rituzena 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 Rituzena. Your doctor may need to take special care during your treatment with 
Rituzena. 
 
If you have granulomatosis with polyangiitis or microscopic polyangiitis 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 Rituzena help to fight infection and you should wait until the infection has passed before you 
are given Rituzena. Also please tell your doctor if you have 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 for travel 
to other countries. Some vaccines should not be given at the same time as Rituzena or in the 
months after you receive Rituzena. Your doctor will check if you should have any vaccines 
before you receive Rituzena. 

 
Children and adolescents 
Talk to your doctor, pharmacist or nurse before you are given this medicine if you, or your child, 
are under 18 years of age. This is because there is not much information about the use of Rituzena 
in children and young people. 

 
Other medicines and Rituzena 
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 Rituzena can affect the way some other medicines work. Also some other medicines can 
affect the way Rituzena 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 Rituzena. This is because some people have a fall in 
their blood pressure while they are being given Rituzena. 

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

 

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If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
you are given Rituzena. 
 
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 Rituzena can transfer 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 Rituzena. You must also do this for 12 months after your last treatment with 
Rituzena. 
Do not breast-feed while you are being treated with Rituzena. Also do not breast-feed for 12 months 
after your last treatment with Rituzena. This is because Rituzena may pass into breast milk. 
 
Driving and using machines 
It is not known whether Rituzena has an effect on you being able to drive or use any tools or 
machines. 
 
 
9. How Rituzena is given  
 
How it is given 
Rituzena 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 Rituzena as a drip (intravenous infusion). 
 
Medicines given before each Rituzena administration 
Before you are given Rituzena, you will be given other medicines (pre-medication) to prevent or 
reduce possible side effects. 
 
How much and how often you will receive your treatment 
 
d) If you are being treated for non-Hodgkin’s Lymphoma 
• If you are having Rituzena alone 

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

• If you are having Rituzena with chemotherapy 
Rituzena will be given to you on the same day as your chemotherapy. This is usually given 

every 3 weeks up to 8 times. 
 
e) If you are being treated for chronic lymphocytic leukaemia 
When you are treated with Rituzena in combination with chemotherapy, you will receive Rituzena 
every 28 days until you have received 6 doses. The chemotherapy should be given after the Rituzena 
infusion. Your doctor will decide if you should receive other treatment at the same time. 
 
 
f) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis  
Treatment with Rituzena uses four separate infusions given at weekly intervals. A corticosteroid 
medicine will usually be given by injection before the start of Rituzena treatment. Corticosteroid 
medicine given by mouth may be started at any time by your doctor to treat your condition. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
10. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 

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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 2 hours of the first infusion you may develop fever, chills and shivering. 
Less frequently, some patients may get pain at the infusion site, blisters, itching, sickness, tiredness, 
headache, breathing difficulties, 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 
infusion reactions might get worse. Tell the person giving you the infusion immediately if you 
develop 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 Rituzena treatment if these reactions are 
serious. 
 
Infections 
Tell your doctor immediately if you get signs of an infection including: 
 
• fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell 
• memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare, 

serious brain infection, which has been fatal (progressive multifocal leukoencephalopathy or 
PML). 

You might get infections more easily during your treatment with Rituzena. 
These are often colds, but there have been cases of pneumonia or urinary infections. These are 
listed below under “Other side effects”. 
 
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: 
c) If you 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 sometimes with fever, or low number of 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 

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• 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 and uneven or fast heart rate 
• high or low blood pressure (low blood pressure especially when standing upright) 
• tightening of the muscles in the airways which causes wheezing (bronchospasm), 

inflammation, irritation in the lungs, throat or sinuses, being short of breath, runny 
nose 

• being sick (vomiting), diarrhoea, pain in the stomach, irritation or ulcers in the throat 
and mouth, problems swallowing, constipation, indigestion 

• eating disorders: not eating enough, leading to weight loss 
• hives, increased sweating, night sweats 
• muscle problems – such as tight muscles, joint or muscle pain, back and neck pain 
• 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 

 
d) If you 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 

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• painful joints or back 
• muscle twitches or shakiness 
• feeling dizzy 
• tremors (shakiness, often in the hands) 
• difficulty sleeping (insomnia) 
• swelling of the hands or ankles 

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

• indigestion 
• constipation 
• skin rashes, including acne or spots 
• flushing or redness of the skin 
• blocked 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 
 
Rituzena may also cause changes in laboratory tests carried out by your doctor. 
 
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. 
 
 

11. How to store Rituzena 
 
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. 
 
 
 
12. Contents of the pack and other information  
 
What Rituzena contains 

• The active ingredient in Rituzena is called rituximab. The vial contains 500 mg of 
rituximab. Each mL of concentrate contains 10 mg of rituximab.  

• The other ingredients are sodium chloride, tri-sodium citrate dihydrate, polysorbate 80 and 

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water for injections. 
 
What Rituzena looks like and contents of the pack 
 
Rituzena is a clear, colourless solution, supplied as a concentrate for solution for infusion in a glass 
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 
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 CVA 
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 CVA 
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 

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Ελλάδα 
ΒΙΑΝΕΞ Α.Ε. 
Τηλ: +30 210 8009111 – 120 
 
España 
Kern Pharma, S.L. 
Tel: +34 93 700 2525 

Österreich 
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.  
Sími: +354 535 7000 
 

Slovenská republika 
EGIS SLOVAKIA spol. s r.o 
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. 

 

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	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