Rixathon

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

▼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 
 
Rixathon 100 mg concentrate for solution for infusion 
Rixathon 500 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Rixathon 100 mg concentrate for solution for infusion 
Each 10 mL vial contains 100 mg of rituximab. 
 
Rixathon 500 mg concentrate for solution for infusion 
Each 50 mL vial contains 500 mg of rituximab. 
 
Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a 
glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and 
heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster 
ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including 
specific viral inactivation and removal procedures. 
 
Excipient with known effect 
This medicinal product contains 2.3 mmol (52.6 mg) sodium per 10 mL vial. 
This medicinal product contains 11.5 mmol (263.2 mg) sodium per 50 mL vial. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
 
Clear, colourless to slightly yellowish liquid. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rixathon is indicated in adults for the following indications: 
 
Non-Hodgkin’s lymphoma (NHL) 
 
Rixathon is indicated for the treatment of previously untreated patients with stage III-IV follicular 
lymphoma in combination with chemotherapy. 
 
Rixathon maintenance therapy is indicated for the treatment of follicular lymphoma patients 
responding to induction therapy. 
 
Rixathon monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma 
who are chemoresistant or are in their second or subsequent relapse after chemotherapy. 
 



3 

Rixathon 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) 
 
Rixathon in combination with chemotherapy is indicated for the treatment of patients with previously 
untreated and relapsed/refractory chronic lymphocytic leukaemia. Only limited data are available on 
efficacy and safety for patients previously treated with monoclonal antibodies including rituximab or 
patients refractory to previous rituximab plus chemotherapy. 
 
See section 5.1 for further information. 
 
Rheumatoid arthritis 
 
Rixathon in combination with methotrexate is indicated for the treatment of adult patients with severe 
active rheumatoid arthritis who have had an inadequate response or intolerance to other 
disease-modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor 
(TNF) inhibitor therapies. 
 
Rituximab has been shown to reduce the rate of progression of joint damage as measured by X-ray and 
to improve physical function, when given in combination with methotrexate. 
 
Granulomatosis with polyangiitis and microscopic polyangiitis 
 
Rixathon, in combination with glucocorticoids, is indicated for the treatment of adult patients with 
severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis 
(MPA). 
 
Pemphigus vulgaris 
 
Rixathon is indicated for the treatment of patients with moderate to severe pemphigus vulgaris (PV). 
 
4.2 Posology and method of administration 
 
Rixathon should be administered under the close supervision of an experienced healthcare 
professional, and in an environment where full resuscitation facilities are immediately available (see 
section 4.4). 
 
Premedication and prophylactic medications 
 
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and 
diphenhydramine, should always be given before each administration of Rixathon. 
 
In patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia, premedication with 
glucocorticoids should be considered if Rixathon is not given in combination with 
glucocorticoid-containing chemotherapy.  
 
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 Rixathon to decrease the 
rate and severity of acute infusion reactions and/or cytokine release syndrome. 
 
In patients with rheumatoid arthritis, granulomatosis with polyangiitis (Wegener’s) or microscopic 
polyangiitis in disease remission or pemphigus vulgaris, premedication with 100 mg intravenous 



4 

methylprednisolone should be completed 30 minutes prior to Rixathon infusions to decrease the 
incidence and severity of infusion related reactions (IRRs). 
 
In patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis, 
methylprednisolone given intravenously for 1 to 3 days at a dose of 1,000 mg per day is recommended 
prior to the first infusion of Rixathon (the last dose of methylprednisolone may be given on the same 
day as the first infusion of Rixathon). This should be followed by oral prednisone 1 mg/kg/day (not to 
exceed 80 mg/day, and tapered as rapidly as possible based on clinical need) during and after the 4 
week induction course of Rixathon treatment. 
 
Pneumocystis jirovecii pneumonia (PCP) prophylaxis is recommended for patients with GPA/MPA or 
PV during and following Rixathon treatment, as appropriate according to local clinical practice 
guidelines. 
 
Posology 
 
It is important to check the medicinal product labels to ensure that the appropriate formulation is being 
given to the patient, as prescribed. 
 
Non-Hodgkin’s lymphoma 
 
Follicular non-Hodgkin's lymphoma 
 
Combination therapy 
The recommended dose of Rixathon 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. 
 
Rixathon should be administered on day 1 of each chemotherapy cycle, after intravenous 
administration of the glucocorticoid component of the chemotherapy if applicable. 
 
Maintenance therapy 

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

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

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



5 

Diffuse large B cell non-Hodgkin's lymphoma 
 
Rixathon 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 rituximab 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 Rixathon are recommended. When Rixathon is given in combination with 
chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be 
applied. 
 
Chronic lymphocytic leukaemia 
 
The recommended dosage of Rixathon 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 Rixathon infusion. 
 
Rheumatoid arthritis 
 
Patients treated with Rixathon must be given the patient alert card with each infusion. 
 
A course of Rixathon consists of two 1,000 mg intravenous infusions. The recommended dosage of 
Rixathon is 1,000 mg by intravenous infusion followed by a second 1,000 mg intravenous infusion 
two weeks later. 
 
The need for further courses should be evaluated 24 weeks following the previous course. Retreatment 
should be given at that time if residual disease activity remains, otherwise retreatment should be 
delayed until disease activity returns. 
 
Available data suggest that clinical response is usually achieved within 16 to 24 weeks of an initial 
treatment course. Continued therapy should be carefully reconsidered in patients who show no 
evidence of therapeutic benefit within this time period. 
 
Granulomatosis with polyangiitis and microscopic polyangiitis 
 
Patients treated with Rixathon must be given the patient alert card with each infusion. 
 
Induction of remission 
The recommended dosage of Rixathon 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). 
 
Maintenance treatment 
Following induction of remission with Rixathon, maintenance treatment should be initiated no sooner 
than 16 weeks after the last rituximab infusion. 
 
Following induction of remission with other standard of care immunosuppressants, Rixathon 
maintenance treatment should be initiated during the 4 week period that follows disease remission.  
 



6 

Rixathon should be administered as two 500 mg IV infusions separated by two weeks, followed by a 
500 mg IV infusion every 6 months thereafter. Patients should receive Rixathon for at least 24 months 
after achievement of remission (absence of clinical signs and symptoms). For patients who may be at 
higher risk for relapse, physicians should consider a longer duration of Rixathon maintenance therapy, 
up to 5 years. 
 
Pemphigus vulgaris 
 
Patients treated with Rixathon must be given the patient alert card with each infusion. 
 
The recommended dosage of Rixathon for the treatment of pemphigus vulgaris is 1000 mg 
administered as an IV infusion followed two weeks later by a second 1000 mg IV infusion in 
combination with a tapering course of glucocorticoids. 
 
Maintenance treatment 
A maintenance infusion of 500 mg IV should be administered at months 12 and 18, and then every 6 
months thereafter if needed, based on clinical evaluation. 
 
Treatment of relapse 
In the event of relapse, patients may receive 1000 mg IV. The healthcare provider should also consider 
resuming or increasing the patient’s glucocorticoid dose based on clinical evaluation.  
 
Subsequent infusions may be administered no sooner than 16 weeks following the previous infusion. 
 
Special populations 
 
Paediatric population 
The safety and efficacy of rituximab in children below 18 years have not been established. No data are 
available. 
 
Elderly 
No dose adjustment is required in elderly patients (aged > 65 years). 
 
Method of administration 
 
Rixathon is for intravenous use. The prepared Rixathon solution should be administered as an 
intravenous infusion through a dedicated line. It should not be administered as an intravenous push or 
bolus. 
 
Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). 
Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or 
hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma 
should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests 
and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted 
until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray 
findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. 
If the same severe adverse reactions occur for a second time, the decision to stop the treatment should 
be seriously considered on a case by case basis. 
 
Mild or moderate infusion-related reactions (IRR) (section 4.8) usually respond to a reduction in the 
rate of infusion. The infusion rate may be increased upon improvement of symptoms. 
 
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. 
 



7 

Subsequent infusions 
 
All indications 
 
Subsequent doses of Rixathon 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. 
 
Rheumatoid arthritis only 
 
Alternative subsequent, faster, infusion schedule 
 
If patients did not experience a serious infusion related reaction with their first or subsequent infusions 
of a dose of 1,000 mg Rixathon administered over the standard infusion schedule, a more rapid 
infusion can be administered for second and subsequent infusions using the same concentration as in 
previous infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250 mg/hour for the first 
30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this 
infusion schedule can be used when administering subsequent infusions. 
 
Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous 
serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the 
more rapid infusion. 
 
4.3 Contraindications 
 
Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia 
 
Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in 
section 6.1. 
 
Active, severe infections (see section 4.4). 
 
Patients in a severely immunocompromised state. 
 
Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis, microscopic 
polyangiitis and pemphigus vulgaris 
 
Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in 
section 6.1. 
 
Active, severe infections (see section 4.4). 
 
Patients in a severely immunocompromised state. 
 
Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease 
(see section 4.4 regarding other cardiovascular diseases). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
In order to improve traceability of biological medicinal products, the name and the batch number of 
the administered product should be clearly recorded. 
 
Progressive multifocal leukoencephalopathy 
 
All patients treated with Rixathon for rheumatoid arthritis, granulomatosis with polyangiitis, 
microscopic polyangiitis or pemphigus vulgaris must be given the patient alert card with each 



8 

infusion. The alert card contains important safety information for patients regarding potential 
increased risk of infections, including progressive multifocal leukoencephalopathy (PML). 
 
Very rare cases of fatal PML have been reported following use of rituximab. Patients must be 
monitored at regular intervals for any new or worsening neurological symptoms or signs that may be 
suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been 
excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of 
neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. 
Consultation with a Neurologist should be considered as clinically indicated. 
 
If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal 
fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered. 
 
The physician should be particularly alert to symptoms suggestive of PML that the patient may not 
notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to 
inform their partner or caregivers about their treatment, since they may notice symptoms that the 
patient is not aware of. 
 
If a patient develops PML, the dosing of Rixathon 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. 
 



9 

Patients with a high tumour burden or with a high number (≥ 25 x 109/L) of circulating malignant cells 
such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome, 
should be treated with extreme caution. These patients should be very closely monitored throughout 
the first infusion. Consideration should be given to the use of a reduced infusion rate for the first 
infusion in these patients or a split dosing over two days during the first cycle and any subsequent 
cycles if the lymphocyte count is still > 25 x 109/L. 
 
Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated with 
rituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in 
10% of patients) see section 4.8. These symptoms are usually reversible with interruption of rituximab 
infusion and administration of an anti-pyretic, an antihistaminic and occasionally oxygen, intravenous 
saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above 
for severe reactions. 
 
Anaphylactic and other hypersensitivity reactions have been reported following the intravenous 
administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity 
reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of 
hypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids, should be 
available for immediate use in the event of an allergic reaction during administration of rituximab. 
Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine 
release syndrome (described above). Reactions attributed to hypersensitivity have been reported less 
frequently than those attributed to cytokine release. 
 
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary 
oedema and acute reversible thrombocytopenia. 
 
Since hypotension may occur during rituximab administration, consideration should be given to 
withholding anti-hypertensive medicinal product 12 hours prior to the Rixathon 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 
Rixathon therapy. 
 
Infections 
Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8). 
Rixathon 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 Rixathon 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 



10 

(HBV) screening should be performed in all patients before initiation of treatment with Rixathon. 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 Rixathon. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should 
consult liver disease experts before start of treatment and should be monitored and managed following 
local medical standards to prevent hepatitis B reactivation. 
 
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during 
post-marketing use of rituximab in NHL and CLL (see section 4.8). The majority of patients had 
received rituximab in combination with chemotherapy or as part of a hematopoietic 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 Rixathon 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, microscopic polyangiitis, and pemphigus 
vulgaris 
 
Methotrexate (MTX) naïve populations with rheumatoid arthritis 
The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit risk 
relationship has not been established. 
 
Infusion-related reactions 
Rituximab is associated with infusion related reactions (IRRs), which may be related to release of 
cytokines and/or other chemical mediators.  
 
Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the 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 Rixathon. 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. 
 



11 

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 Rixathon. 
 
There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III) 
or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence of 
pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been 
observed, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history, 
and those who experienced prior cardiopulmonary adverse reactions, the risk of cardiovascular 
complications resulting from infusion reactions should be considered before treatment with Rixathon 
and patients closely monitored during administration. Since hypotension may occur during rituximab 
infusion, consideration should be given to withholding anti-hypertensive medicinal products 12 hours 
prior to the Rixathon infusion. 
 
IRRs for patients with granulomatosis with polyangiitis, microscopic polyangiitis and pemphigus 
vulgaris were consistent with 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). Rixathon 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 Rixathon. 
 
Patients reporting signs and symptoms of infection following Rixathon therapy should be promptly 
evaluated and treated appropriately. Before giving a subsequent course of Rixathon 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 Rixathon. 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 



12 

Measure blood neutrophils prior to each course of Rixathon, 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 Rixathon, treatment should be permanently discontinued. 
 
Immunisation 
Physicians should review the patient’s vaccination status and follow current immunisation guidelines 
prior to Rixathon therapy. Vaccination should be completed at least 4 weeks prior to first 
administration of Rixathon. 
 
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 Rixathon or whilst 
peripherally B cell depleted. 
 
Patients treated with Rixathon 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 Rixathon 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. 
 
Sodium 
 
This medicinal product contains 2.3 mmol (or 52.6 mg) sodium per 10 mL vial up to 23.06 mmol (or 
530.1 mg) sodium per dose. This medicinal product contains 11.5 mmol (263.2 mg) sodium per 50 mL 
vial. To be taken into consideration by patients on a controlled sodium diet. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Currently, there are limited data on possible interactions with other medicinal products and rituximab. 
 



13 

In CLL patients, co-administration with rituximab did not appear to have an effect on the 
pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of 
fludarabine and cyclophosphamide on the pharmacokinetics of rituximab. 
 
Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in 
rheumatoid arthritis patients. 
 
Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have 
allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal 
antibodies. 
 
In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic 
DMARD following rituximab. In these patients the rate of clinically relevant infection while on 
rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment 
with the biologic DMARD. 
 
4.6 Fertility, pregnancy and lactation 
 
Contraception in males and females  
 
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing 
potential should use effective contraceptive methods during and for 12 months following treatment 
with Rixathon. 
 
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 Rixathon 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 breast-feed while treated with Rixathon and for 12 months following Rixathon treatment. 
 
Fertility 
 
Animal studies did not reveal deleterious effects of rituximab on reproductive organs. 
 
4.7 Effects on ability to drive and use machines 
 
Rituximab may have a minor influence on the ability to drive and use machines. Dizziness may occur 
following administration of rituximab (see section 4.8). 
 



14 

4.8 Undesirable effects 
 
Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia 
 
Summary of the safety profile 
 
The overall safety profile of rituximab in non-Hodgkin’s lymphoma and chronic lymphocytic 
leukaemia 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 (ADRs) were: 
• IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4. 
• Infections, see section 4.4. 
• Cardiovascular events, see section 4.4. 
 
Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.) 
 
Tabulated list of adverse reactions 
 
The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy are 
summarised in Table 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 < 1/1,000) and 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 postmarketing 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 
infections, 
viral 
infections, 
+bronchitis 

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

 Serious viral 
infection2 
Pneumocystis 
jirovecii 

PML  

Blood and Neutropenia Anaemia, Coagulation  Transient Late 



15 

System Organ 
Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

lymphatic 
system 
disorders 

, leucopenia, 
+febrile 
neutropenia, 
+thrombocyt
openia 

+pancytopenia, 
+granulocytopenia 

disorders, 
aplastic 
anaemia, 
haemolytic 
anaemia, 
lymphadeno
pathy 

increase in 
serum IgM 
levels3 

neutropenia3 

Immune 
system 
disorders 

Infusion 
related 
reactions4, 
angioedema 

Hypersensitivity  Anaphylaxis Tumour 
lysis 
syndrome, 
cytokine 
release 
syndrome4, 
serum 
sickness 

Infusion-
related acute 
reversible 
thrombocytop
enia4 

Metabolism 
and nutrition 
disorders 

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

    

Psychiatric 
disorders 

  Depression, 
nervousness 

   

Nervous 
system 
disorders 

 Paraesthesia, 
hypoaesthesia, 
agitation, 
insomnia, 
vasodilatation, 
dizziness, anxiety 

Dysgeusia  Peripheral 
neuropathy
, facial 
nerve 
palsy5 

Cranial 
neuropathy, 
loss of other 
senses5 

Eye disorders  Lacrimation 
disorder, 
conjunctivitis 

  Severe 
vision loss5 

 

Ear and 
labyrinth 
disorders 

 Tinnitus, ear pain    Hearing loss5 

Cardiac 
disorders 

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

+Left 
ventricular 
failure, 
+supraventri
cular 
tachycardia, 
+ventricular 
tachycardia, 
+angina, 
+myocardial 
ischaemia, 
bradycardia 

Severe 
cardiac 
disorders 4 and 
6 

Heart 
failure4and 6 

 

Vascular 
disorders 

 Hypertension, 
orthostatic 
hypotension, 
hypotension 

  Vasculitis 
(predomin
ately 
cutaneous), 
leukocytoc
lastic 
vasculitis 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

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

Asthma, 
bronchiolitis 
obliterans, 
lung 
disorder, 

Interstitial 
lung disease7 

Respirator
y failure4 

Lung 
infiltration 



16 

System Organ 
Class 

Very 
Common Common Uncommon Rare Very Rare Not known 

rhinitis hypoxia 
Gastrointestin
al disorders 

Nausea Vomiting, 
diarrhoea, 
abdominal pain, 
dysphagia, 
stomatitis, 
constipation, 
dyspepsia, 
anorexia, throat 
irritation 

Abdominal 
enlargement 

 Gastro-
intestinal 
perforation
7 

 

Skin and 
subcutaneous 
tissue 
disorders 

Pruritis, 
rash, 
+alopecia 

Urticaria, 
sweating, night 
sweats, +skin 
disorder 

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

 

Musculoskelet
al and 
connective 
tissue 
disorders 

 Hypertonia, 
myalgia, 
arthralgia, back 
pain, neck pain, 
pain 

    

Renal and 
urinary 
disorders 

    Renal 
failure4 

 

General 
disorders and 
administratio
n site 
conditions 

Fever , 
chills, 
asthenia, 
headache 

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

Infusion site 
pain 

   

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. 
 
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 



17 

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. 
 
Description of selected adverse reactions 
 
Infections 
Rituximab induces B-cell depletion in about 70-80% of patients, but was associated with decreased 
serum immunoglobulins only in a minority of patients. 
 
Localised candida infections as well as Herpes zoster were reported at a higher incidence in the 
rituximab-containing arm of randomised studies. Severe infections were reported in about 4% of 
patients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade 
3 or 4 infections, were observed during rituximab maintenance treatment up to 2 years when compared 
to observation. There was no cumulative toxicity in terms of infections reported over a 2-year 
treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, 
some of which were fatal, have been reported with rituximab treatment. The majority of patients had 
received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell 
transplant. Examples of these serious viral infections are infections caused by the herpes viruses 
(Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal 
leukoencephalopathy [PML]) and hepatitis C virus. Cases of fatal PML that occurred after disease 
progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, 
have been reported, the majority of which were in patients receiving rituximab in combination with 
cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis 
B infection (reactivation and primary infection) was 2% in R-FC vs. 0% FC. Progression of Kaposi’s 
sarcoma has been observed in rituximab-exposed patients with pre-existing Kaposi’s sarcoma. These 
cases occurred in non-approved indications and the majority of patients were HIV positive. 
 
Haematologic adverse reactions 
In clinical trials with rituximab monotherapy given for 4 weeks, haematological abnormalities 
occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia 
was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During 
rituximab maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and neutropenia 
(10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to observation. The 
incidence of thrombocytopenia was low (< 1%, grade 3/4) and was not different between treatment 
arms. During the treatment course in studies with rituximab in combination with chemotherapy, 
grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), neutropenia (R-CVP 
24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated 
CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with 
higher frequencies when compared to chemotherapy alone. However, the higher incidence of 
neutropenia in patients treated with rituximab and chemotherapy was not associated with a higher 
incidence of infections and infestations compared to patients treated with chemotherapy alone. Studies 
in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients 
treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1 x 109/L 
between day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count 
below 1 x 109/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 



18 

71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of 
patients in the R-FC group compared to 9% of patients in the FC group. 
 
In studies of rituximab in patients with Waldenstrom’s macroglobulinaemia, transient increases in 
serum IgM levels have been observed following treatment initiation, which may be associated with 
hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline 
level within 4 months. 
 
Cardiovascular adverse reactions 
Cardiovascular reactions during clinical trials with rituximab monotherapy were reported in 18.8% of 
patients with the most frequently reported events being hypotension and hypertension. Cases of 
grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris 
during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac 
disorders was comparable between patients treated with rituximab and observation. Cardiac events 
were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left 
ventricular failure, myocardial ischaemia) in 3% of patients treated with rituximab compared to < 1% 
on observation. In studies evaluating rituximab in combination with chemotherapy, the incidence of 
grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia 
and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the 
CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a rituximab 
infusion or were associated with predisposing conditions such as fever, infection, acute myocardial 
infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP 
and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart 
failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall 
incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and 
in the relapsed/refractory study (4% R-FC, 4% FC). 
 
Respiratory system 
Cases of interstitial lung disease, some with fatal outcome have been reported. 
 
Neurologic disorders 
During the treatment period (induction treatment phase comprising of R-CHOP for at most eight 
cycles), four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experienced 
thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference 
between the treatment groups in the incidence of other thromboembolic events. In contrast, three 
patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the 
follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low both 
in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC). 
 
Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior 
leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual 
disturbance, headache, seizures and altered mental status, with or without associated hypertension. A 
diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognized 
risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, 
immunosuppressive therapy and/or chemotherapy. 
 
Gastrointestinal disorders 
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving 
rituximab for treatment of non-Hodgkin 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 



19 

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). 
 
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. 
 
Experience from rheumatoid arthritis 
 
Summary of the safety profile 
 
The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from 
clinical trials and from post-marketing surveillance. 
 
The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) is 
summarised in the sections below. In clinical trials more than 3,100 patients received at least one 
treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 
2,400 patients received two or more courses of treatment with over 1,000 having received 5 or more 
courses. The safety information collected during post marketing experience reflects the expected 
adverse reaction profile as seen in clinical trials for rituximab (see section 4.4). 
 
Patients received 2 x 1,000 mg of rituximab separated by an interval of two weeks; in addition to 
methotrexate (10 – 25 mg/week). Rituximab infusions were administered after an intravenous infusion 
of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days. 
 
Tabulated list of adverse reactions 
 
Adverse reactions are listed in Table 2. 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. 



20 

 
The most frequent adverse reactions considered due to receipt of rituximab 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 ADRs reported in clinical trials or during postmarketing 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 
ickness-like 
reaction 

Immune system 
disorders 

Infusion-
related 
reactions3 
(hypertension, 
nausea, rash, 
pyrexia, 
pruritus, 
urticaria, 
throat 
irritation, hot 
flush, 
hypotension, 
rhinitis, rigors, 
tachycardia, 
fatigue, 
oropharyngeal 
pain, 
peripheral 
oedema, 
erythma) 

 Infusion-
related 
reactions3 
(generalised 
oedema, 
bronchospas
m, wheezing, 
laryngeal 
oedema, 
angioneuroti
c oedema, 
generalised 
pruritus, 
anaphylaxis, 
anaphylactoi
d reaction) 

  

General 
disorders and 
administration 
site conditions 

Metabolism and 
nutrition 
disorders 

 Hypercholestero
lemia 

   

Psychiatric 
disorders 

 Depression, 
anxiety 

   

Nervous system 
disorders 

Headache Paraesthesia, 
migraine, 
dizziness, 
sciatica 

   

Cardiac 
disorders 

   Angina 
pectoris, 
atrial 
fibrillation, 
heart failure, 
myocardial 
infarction 

Atrial flutter 



21 

System Organ 
Class 

Very 
Common Common Uncommon Rare Very rare 

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 

Musculoskeletal 
and connective 
tissue disorders 

 Arthralgia / 
musculoskeletal 
pain, 
osteoarthritis, 
bursitis 

   

Investigations Decreased 
IgM 
levels4 

Decreased IgG 
levels4 

   

1 Frequency category derived from laboratory values collected as part of routine laboratory monitoring 
in clinical trials 
2 Frequency category derived from post-marketing data. 
3 Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. 
IRRs may occur as a result of hypersensitivity and/or to the mechanism of action. 
4 Includes observations collected as part of routine laboratory monitoring. 
5 Includes fatal cases 

 
Multiple courses 
Multiple courses of treatment are associated with a similar ADR profile to that observed following 
first exposure. The rate of all ADRs following first rituximab exposure was highest during the first 
6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the first 
treatment course), RA exacerbation and infections, all of which were more frequent in the first 
6 months of treatment. 
 
Description of selected adverse reactions 
 
Infusion-related reactions 
The most frequent ADRs following receipt of rituximab in clinical studies were IRRs (refer to 
Table 2). 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% 
(17/3,189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due 
to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal 
decreased by course and were rare from course 3 onwards. Premedication with intravenous 
glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). 
Severe IRRs with fatal outcome have been reported in the post-marketing setting. 
 
In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with rheumatoid 
arthritis, patients with moderate-to-severe active RA who did not experience a serious IRR during or 
within 24 hours of their first studied infusion were allowed to receive a 2-hour intravenous infusion of 
rituximab. Patients with a history of a serious infusion reaction to a biologic therapy for RA were 



22 

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 
intravenous 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 RA 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% (13/1,382) of rituximab treated patients and 
0.27% (2/731) of placebo patients developed severe neutropenia. 
 
Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported 
in the post-marketing setting, some of which were associated with fatal infections. 
 
Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Laboratory abnormalities 
Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA 
patients treated with 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 



23 

immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric 
patients are unknown. 
 
Experience from granulomatosis with polyangiitis and microscopic polyangiitis 
 
Induction of remission 
Ninety-nine patients were treated for induction of remission of GPA and MPA in a clinical trial with 
rituximab (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1). 
 
The ADRs listed in Table 3 were all adverse events which occurred at an incidence of ≥ 5% in the 
rituximab group and at a higher frequency than the comparator group. 
 
Table 3 Adverse drug reactions occurring at 6-months in ≥ 5% of patients receiving 

rituximab for induction of remission of GPA and MPA, and at a higher frequency 
than the comparator group. 

Body System 
 

Rituximab 
 

Adverse event (n=99) 
Infections and infestations 

Urinary tract infection 7% 
Bronchitis 5% 
Herpes zoster 5% 
Nasopharyngitis 5% 

Blood and lymphatic system disorders 
Thrombocytopenia 7% 

Immune system disorders 
Cytokine release syndrome 5% 

Metabolism and nutrition disorders 
Hyperkalaemia 5% 

Psychiatric disorders 
Insomnia 14% 

Nervous system disorders 
Dizziness 10% 
Tremor 10% 

Vascular disorders 
Hypertension 12% 
Flushing 5% 

Respiratory, thoracic and mediastinal disorders 
Cough 12% 
Dyspnoea 11% 
Epistaxis 11% 
Nasal congestion 6% 

Gastrointestinal disorders 
Diarrhoea 18% 
Dyspepsia 6% 
Constipation 5% 

Skin and subcutaneous tissue disorders 
Acne 7% 

Musculoskeletal and connective tissue disorders 
Muscle spasms 18% 
Arthralgia 15% 
Back pain 10% 
Muscle weakness 5% 
Musculoskeletal pain 5% 
Pain in extremities 5% 



24 

Body System 
 

Rituximab 
 

Adverse event (n=99) 
General disorders and administration site conditions 

Peripheral oedema 16% 
Investigations 

Decreased haemoglobin 6% 
 
Maintenance treatment 
In a further clinical study, a total of 57 severe, active GPA and MPA patients in disease remission 
were treated with rituximab for the maintenance of remission (see section 5.1). 
 
Table 4 Adverse drug reactions occurring in ≥ 5% of patients receiving rituximab for 

maintenance treatment of GPA and MPA, and at a higher frequency than the 
comparator group 

 
System Organ Class 
Adverse drug reaction1 

Rituximab  
(n=57) 

Infections and infestations   
Bronchitis 14% 
Rhinitis 5% 
General disorders and administration 
site conditions  

Pyrexia 9% 
Influenza-like illness 5% 
Oedema peripheral 5% 
Gastrointestinal disorders   
Diarrhoea 7% 
Respiratory, thoracic and mediastinal 
disorders  

Dyspnoea 9% 
Injury, poisoning and procedural 
complications  

Infusion-related reactions2 12% 
1 Events were considered ADRs only after thorough assessment and where a 
causal relationship between the medicinal product and the adverse event was at 
least a reasonable possibility. 
2Details on infusion related reactions are provided in the description of selected 
adverse drug reactions section. 
 
The overall safety profile was consistent with the well-established safety profile for rituximab in 
approved autoimmune indications, including GPA/MPA. Overall, 4% of patients in the rituximab arm 
experienced adverse events leading to discontinuation. Most adverse events in the rituximab arm were 
mild or moderate in intensity. No patients in the rituximab arm had fatal adverse events. 
 
The most commonly reported events considered as ADRs were infusion-related reactions and 
infections.   
 
In a long-term observational safety study, 97 GPA/MPA patients received treatment with rituximab 
(mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician’s standard practice 
and discretion.  The overall safety profile was consistent with the well-established safety profile of 
rituximab in RA and GPA/MPA and no new adverse drug reactions were reported.    
 
Description of selected adverse reactions 
 
Infusion-related reactions 



25 

In the clinical trial studying induction of remission with severe active GPA and MPA, IRRs were 
defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-
related by investigators in the safety population. Of the ninety nine patients treated with rituximab, 12 
(12%) experienced at least one IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs 
included cytokine release syndrome, flushing, throat irritation, and tremor. Rituximab was given in 
combination with intravenous glucocorticoids which may reduce the incidence and severity of these 
events. 
 
In the maintenance therapy clinical trial, 7/57 (12%) patients in the rituximab arm experienced at least 
one infusion-related reaction. The incidence of IRR symptoms was highest during or after the first 
infusion (9%) and decreased with subsequent infusions (<4%). All IRR symptoms were mild or 
moderate and most of them were reported from the SOCs Respiratory, Thoracic and Mediastinal 
Disorders and Skin and Subcutaneous Tissue disorders.  
 
Infections 
In the clinical trial on induction of remission, which included 99 rituximab-treated 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%. 
 
In the maintenance therapy clinical trial, 30/57 (53%) patients in the rituximab arm experienced 
infections. The incidence of all grade infections was similar between the arms. Infections were 
predominately mild to moderate. The most common infections in the rituximab arm included upper 
respiratory tract infections, gastroenteritis, urinary tract infections and herpes zoster. The incidence of 
serious infections was similar in both arms (approximately 12%). The most commonly reported 
serious infection in the rituximab group was mild or moderate bronchitis. 
 
Malignancies 
In the clinical trial on induction of remission, 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. 
 
Cardiovascular adverse reactions 
In the clinical trial on induction of remission, 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 
postmarketing setting. 
 



26 

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. The rate 
of overall infections and serious infections was not increased after the development of low IgA, IgG or 
IgM. 
 
In the induction of remission clinical trial, at 6 months, in the rituximab group, 27%, 58% and 51% of 
patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, 
respectively compared to 25%, 50% and 46% in the cyclophosphamide group.  
 
In the maintenance therapy clinical trial, no clinically meaningful differences between the two 
treatment arms or decreases in total immunoglobulin, IgG, IgM or IgA levels were observed 
throughout the trial. 
 
Neutropenia 
In the induction of remission clinical trial,  24% of patients in the rituximab group (single course) and 
23% of patients in the cyclophosphamide group developed CTC grade 3 or greater neutropenia. 
Neutropenia was not associated with an observed increase in serious infection in rituximab-treated 
patients.  
 
In the maintenance therapy clinical trial, the incidence of all-grade neutropenia was 0% for rituximab-
treated patients vs 5% for azathioprine treated patients. 
 
Skin and subcutaneous tissue disorders 
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal 
outcome, have been reported very rarely. 
 
Experience from pemphigus vulgaris 
 
Summary of the safety profile 
 
The safety profile of rituximab in combination with short-term, low-dose glucocorticoids in the 
treatment of patients with pemphigus vulgaris was studied in a Phase 3, randomised, controlled, 
multicenter, open-label study in pemphigus patients that included 38 pemphigus vulgaris (PV) patients 
randomised to the rituximab group. Patients randomised to the rituximab group received an initial 
1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15. Maintenance doses of 
500 mg IV were administered at months 12 and 18. Patients could receive 1000 mg IV at the time of 
relapse (see section 5.1).   

The safety profile of rituximab in patients with PV was consistent with that observed in RA and 
GPA/MPA patients.  
 
Tabulated list of adverse reactions 
 
Adverse drug reactions presented in Table 5 were adverse events which occurred at a rate of  ≥ 5% 
among rituximab-treated PV patients, with a  ≥ 2% absolute difference in incidence between the 
rituximab-treated group and the standard-dose prednisone group up to month 24. No patients were 
withdrawn due to ADRs. 
 
Table 5 Adverse drugs reactions for rituximab-treated pemphigus vulgaris patients in the 

clinical study up to month 24 
 
System Organ Class 
Adverse drug reaction 

rituximab + low-dose prednisone 
(n = 38) 

Injury, Poisoning and Procedural  
Complications 
Infusion-related reactions* 58% 



27 

Skin and Subcutaneous Tissue  
Disorders 
Alopecia 13% 
Pruritus 5% 
Urticaria 5% 
Skin disorder 5% 
Psychiatric Disorders 
Persistent depressive disorder 13% 
Major depression 5% 
Irritability 5% 
Infections and Infestations 
Herpes virus infection 8% 
Herpes zoster 5% 
Oral herpes 5% 
Conjunctivitis 5% 
General Disorders and Administration  
Site Conditions 
Fatigue 8% 
Pyrexia 5% 
Nervous System Disorders 
Headache 5% 
Dizziness 5% 
Gastrointestinal Disorders 
Abdominal pain upper 5% 
Cardiac Disorders 
Tachycardia 5% 
Musculoskeletal and Connective Tissue 
Disorders 
Musculoskeletal pain 5% 
Neoplasms Benign, Malignant and  
Unspecified (incl cysts and polyps) 
Skin papilloma 5% 
* Infusion-related reactions included symptoms collected on the next scheduled visit 
after each infusion, and adverse events occurring on the day of or one day after the 
infusion.  The most common infusion-related reaction symptoms/Preferred Terms 
included headaches, chills, high blood pressure, nausea, asthenia and pain.  
 
Description of selected adverse reactions 
 
Infusion-related reactions 
Infusion-related reactions in the pemphigus vulgaris clinical study were common (58%). Nearly all 
infusion-related reactions were mild to moderate. The proportion of patients experiencing an infusion- 
related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) 
following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from 
treatment due to infusion-related reactions. Symptoms of infusion-related reactions were similar in 
type and severity to those seen in RA and GPA/MPA patients. 
 
Infections 
Fourteen patients (37%) in the rituximab group experienced treatment-related infections compared to 
15 patients (42%) in the standard-dose prednisone group. The most common infections in the 
rituximab group were herpes simplex and zoster infections, bronchitis, urinary tract infection, fungal 
infection and conjunctivitis. Three patients (8%) in the rituximab group experienced a total of 5 
serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, 
lung infection, Staphylococcal sepsis) and one patient (3%) in the standard-dose prednisone group 
experienced a serious infection (Pneumocystis jirovecii pneumonia).  
 



28 

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 5,000 mg (2,250 mg/m²), tested in a dose escalation study in patients with chronic lymphocytic 
leukaemia. No additional safety signals were identified. 
 
Patients who experience overdose should have immediate interruption of their infusion and be closely 
monitored. 
 
In the post-marketing setting five cases of rituximab overdose have been reported. Three cases had no 
reported adverse event. The two adverse events that were reported were flu-like symptoms, with a 
dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02 
 
Rixathon 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 internalise upon antibody 
binding and is not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen 
and, thus, does not compete for antibody binding. 
 
The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can 
recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated 
cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and 
antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the 
surface of granulocytes, macrophages and NK cells. Rituximab binding to CD 20 antigen on B 
lymphocytes has also been demonstrated to induce cell death via apoptosis. 
 
Peripheral B cell counts declined below normal following completion of the first dose of rituximab. In 
patients treated for haematological malignancies, B cell recovery began within 6 months of treatment 
and generally returned to normal levels within 12 months after completion of therapy, although in 
some patients this may take longer (up to a median recovery time of 23 months post-induction 
therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was 
observed following two infusions of 1,000 mg rituximab separated by a 14 day interval. Peripheral 
blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the 
majority of patients by week 40, whether rituximab was administered as monotherapy or in 
combination with methotrexate. A small proportion of patients had prolonged peripheral B cell 
depletion lasting 2 years or more after their last dose of rituximab. In patients with granulomatosis 



29 

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 
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 multi-centre, 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 multi-centre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular 
B cell NHL, who had achieved an objective clinical response to a prior course of 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%; CR 10%, PR 28%) 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, 



30 

vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1 -
 5) every 3 weeks for 8 cycles or rituximab 375 mg/m2 in combination with CVP (R-CVP). Rituximab 
was administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP, 
159 CVP) received therapy and were analysed for efficacy. The median follow up of patients was 
53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment 
failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour 
response (CR, CRu, PR) was significantly higher (p  < 0.0001 Chi-Square test) in the R-CVP group 
(80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to 
disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively 
(p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and 
was 13.5 months in the CVP group (p < 0.0001, log-rank test). 
 
The difference between the treatment groups with respect to overall survival showed a significant 
clinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were 80.9% 
for patients in the R-CVP group compared to 71.1% for patients in the CVP group. 
 
Results from three other randomised trials using rituximab in combination with chemotherapy regimen 
other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant improvements 
in response rates, time-dependent parameters as well as in overall survival. Key results from all four 
studies are summarised in Table 6. 
 
Table 6 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 
 
Maintenance therapy 
 
Previously untreated follicular lymphoma 
In a prospective, open label, international, multi-centre, phase III trial 1,193 patients with previously 
untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP 
(n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1,078 patients responded 
to induction therapy, of which 1,018 were randomised to rituximab maintenance therapy (n=505) or 
observation (n=513). The two treatment groups were well balanced with regards to baseline 



31 

characteristics and disease status. Rituximab maintenance treatment consisted of a single infusion of 
rituximab at 375 mg/m2 body surface area given every 2 months until disease progression or for a 
maximum period of two years. 
 
The pre-specified primary analysis was conducted at a median observation time of 25 months from 
randomization, maintenance therapy with rituximab resulted in a clinically relevant and statistically 
significant improvement in the primary endpoint of investigator assessed progression-free survival 
(PFS) as compared to observation in patients with previously untreated follicular lymphoma (Table 7). 
 
Significant benefit from maintenance treatment with rituximab was also seen for the secondary 
endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next 
chemotherapy (TNCT) and overall response rate (ORR) in the primary analysis (Table 7).  
 
Data from extended follow up of patients in the study (median follow-up 9 years) confirmed the long-
term benefit of rituximab maintenance therapy in terms of PFS, EFS, TNLT, and TNCT (Table 7). 
 
Table 7 Overview of efficacy results for rituximab maintenance vs. observation at the 

protocol-defined primary analysis and after 9 years median follow-up (final 
analysis) 

 Primary analysis  
(median FU: 25 months) 

 
 

Final analysis  
(median FU:9.0 years) 

 Observation 
N=513 

Rituximab 
N=505 

 

Observation 
N=513 

Rituximab 
N=505 

 

Primary efficacy  
Progression-free survival (median)  
log-rank p value 
hazard ratio (95% CI) 
risk reduction 

 

 
NR                    NR 

<0.0001 
0.50 (0.39, 0.64) 

50% 

 
4.06 years           10.49 years 

<0.0001 
0.61 (0.52, 0.73) 

39% 
Secondary efficacy  
Overall survival (median)  
log-rank p value 
hazard ratio (95% CI) 
risk reduction 

 

 
NR                    NR 

0.7246 
0.89 (0.45, 1.74) 

11% 

 
NR                    NR 

0.7948 
1.04 (0.77, 1.40) 

-6% 
Event-free survival (median)  
log-rank p value 
hazard ratio (95% CI) 
risk reduction 

38 months           NR 
<0.0001 

0.54 (0.43, 0.69) 
46% 

4.04 years           9.25 years 
<0.0001 

0.64 (0.54, 0.76) 
36% 

TNLT (median)  
log-rank p value 
hazard ratio (95% CI) 
risk reduction 

NR                    NR 
0.0003 

0.61 (0.46, 0.80) 
39% 

6.11 years           NR 
<0.0001 

0.66 (0.55, 0.78) 
34% 

TNCT (median)  
log-rank p value 
hazard ratio (95% CI) 
risk reduction 

NR                    NR 
0.0011 

0.60 (0.44, 0.82) 
40% 

9.32 years           NR 
0.0004 

0.71 (0.59, 0.86) 
39% 

Overall response rate*  
chi-squared test p value  
odds ratio (95% CI)  

55%                    74% 
<0.0001 

2.33 (1.73, 3.15) 

61%                    79% 
<0.0001 

2.43 (1.84, 3.22) 
Complete response (CR/CRu) rate*  
chi-squared test p value  
odds ratio (95% CI) 

48%                    67% 
<0.0001 

2.21 (1.65, 2.94) 

53%                    67% 
<0.0001 

2.34 (1.80, 3.03) 
* at end of maintenance/observation; final analysis results based on median follow-up of 73 months.  
FU: follow-up; NR: not reached at time of clinical cut off, TNCT: time to next chemotherapy treatment; TNLT: time to next anti 
lymphoma treatment. 
 
Rituximab maintenance treatment provided consistent benefit in all predefined subgroups tested: 
gender (male, female), age (< 60 years, >= 60 years), FLIPI score (<=1, 2 or >= 3), induction therapy 
(R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment (CR, 
CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less pronounced 
effect in elderly patients (> 70 years of age), however sample sizes were small. 



32 

 
Relapsed/Refractory follicular lymphoma 
 
In a prospective, open label, international, multi-centre, phase III trial, 465 patients with 
relapsed/refractory follicular lymphoma were randomised in a first step to induction therapy with 
either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or rituximab plus 
CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard to baseline 
characteristics and disease status. A total of 334 patients achieving a complete or partial remission 
following induction therapy were randomised in a second step to rituximab maintenance therapy 
(n=167) or observation (n=167). Rituximab maintenance treatment consisted of a single infusion of 
rituximab at 375 mg/m2 body surface area given every 3 months until disease progression or for a 
maximum period of two years. 
 
The final efficacy analysis included all patients randomised to both parts of the study. After a median 
observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly 
improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to 
CHOP (see Table 8). 
 
Table 8 Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months 

median observation time) 
 

 CHOP R-CHOP p-value Risk reduction1) 
Primary efficacy 

ORR2) 
CR2) 
PR2) 

 
74% 
16% 
58% 

 
87% 
29% 
58% 

 
0.0003 
0.0005 
0.9449 

 
NA 
NA 
NA 

1) Estimates were calculated by hazard ratios 
2) Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the 

trend test of CR versus PR versus non-response (p < 0.0001) 
Abbreviations: NA, not available; ORR: overall response rate; CR: complete response; PR: partial response 
 
For patients randomised to the maintenance phase of the trial, the median observation time was 
28 months from maintenance randomisation. Maintenance treatment with rituximab led to a clinically 
relevant and statistically significant improvement in the primary endpoint, PFS, (time from 
maintenance randomisation to relapse, disease progression or death) when compared to observation 
alone (p < 0.0001 log-rank test).The median PFS was 42.2 months in the rituximab maintenance arm 
compared to 14.3 months in the observation arm. Using a cox regression analysis, the risk of 
experiencing progressive disease or death was reduced by 61% with rituximab maintenance treatment 
when compared to observation (95% CI; 45% - 72%). Kaplan-Meier estimated progression- free rates 
at 12 months were 78% in the rituximab maintenance group vs. 57% in the observation group. An 
analysis of overall survival confirmed the significant benefit of rituximab maintenance over 
observation (p=0.0039 log-rank test). Rituximab maintenance treatment reduced the risk of death by 
56% (95% CI; 22% - 75%). 
 
Table 9 Maintenance phase: overview of efficacy results rituximab vs. observation 

(28 months median observation time) 
 
Efficacy parameter Kaplan-Meier estimate of 

median time to event (months) 
Risk 

reduction 
Observation 

(N=167) 
Rituximab 

(N=167) 
Log-rank 
p value 

Progression-free survival 
(PFS) 

14.3 42.2 < 0.0001 61% 

Overall survival NR NR 0.0039 56% 
Time to new lymphoma 
treatment 
 

20.1 
 
 

38.8 
 
 

< 0.0001 
 
 

50% 
 
 



33 

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

Risk 
reduction 

Observation 
(N=167) 

Rituximab 
(N=167) 

Log-rank 
p value 

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

CHOP 
R-CHOP 

CR 
PR 

 
 
 
OS 

CHOP 
R-CHOP 

 
 

11.6 
22.1 
14.3 
14.3 

 
 
 
 

NR 
NR 

 
 

37.5 
51.9 
52.8 
37.8 

 
 
 
 

NR 
NR 

 
 

< 0.0001 
0.0071 
0.0008 

< 0.0001 
 
 
 
 

0.0348 
0.0482 

 
 

71% 
46% 
64% 
54% 

 
 
 
 

55% 
56% 

NR: not reached; a: only applicable to patients achieving a CR 
 
The benefit of rituximab maintenance treatment was confirmed in all subgroups analysed, regardless 
of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) 
(Table 9). Rituximab maintenance treatment significantly prolonged median PFS in patients 
responding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p < 0.0001) as well 
as in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). 
Although subgroups were small, rituximab maintenance treatment provided a significant benefit in 
terms of overall survival for both patients responding to CHOP and patients responding to R-CHOP, 
although longer follow-up is required to confirm this observation. 
 
Diffuse large B cell non-Hodgkin’s lymphoma 
 
In a randomised, open-label trial, a total of 399 previously untreated elderly patients 
(age 60 to 80 years) with diffuse large B cell lymphoma received standard CHOP chemotherapy 
(cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 
2 mg on day 1, and prednisolone 40 mg/m2/day on days 1-5) every 3 weeks for eight cycles, or 
rituximab 375 mg/m2 plus CHOP (R-CHOP). Rituximab was administered on the first day of the 
treatment cycle. 
 
The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a 
median follow-up duration of approximately 31 months. The two treatment groups were well balanced 
in baseline disease characteristics and disease status. The final analysis confirmed that R-CHOP 
treatment was associated with a clinically relevant and statistically significant improvement in the 
duration of event-free survival (the primary efficacy parameter; where events were death, relapse or 
progression of lymphoma, or institution of a new anti-lymphoma treatment) (p=0.0001). Kaplan Meier 
estimates of the median duration of event-free survival were 35 months in the R-CHOP arm compared 
to 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months, estimates for 
overall survival were 68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequent 
analysis of the duration of overall survival, carried out with a median follow-up duration of 60 months, 
confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), representing a risk reduction of 
32%. 
 
The analysis of all secondary parameters (response rates, progression-free survival, disease-free 
survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The 
complete response rate after cycle 8 was 76.2% in the R-CHOP group and 62.4% in the CHOP group 
(p=0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by 51%. In all 
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 



34 

respectively. R-CHOP was associated with improvements in outcome for both high- and low-risk 
patients according to age adjusted IPI. 
 
Clinical laboratory findings 
 
Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of 
356 patients evaluated for anti-drug antibody (ADA), 1.1% (4 patients) were positive. 
 
Chronic lymphocytic leukaemia 
 
In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients with 
relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, 
cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or rituximab in combination with 
FC (R-FC). Rituximab was administered at a dosage of 375 mg/m2 during the first cycle one day prior 
to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients 
were excluded from the study in relapsed/refractory CLL if they had previously been treated with 
monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for 
at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 
407 FC) for the first-line study (Table 10a and Table 10b) and 552 patients (276 R-FC, 276 FC) for the 
relapsed/refractory study (Table 11) 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 10a). 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 10b). 
 
Table 10a 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 
 



35 

Table 10b First-line treatment of chronic lymphocytic leukaemia 
Hazard ratios of progression-free survival according to Binet stage (ITT) – 
48.1 months median observation time 

 
Progression-free survival (PFS) Number of 

patients 
Hazard ratio 

(95% CI) 
p-value 

(Wald test, 
not adjusted) FC R-FC 

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

CI: Confidence Interval 
 
In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 
30.6 months in the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). The 
benefit in terms of PFS was observed in almost all patient subgroups analysed according to disease 
risk at baseline. A slight but not significant improvement in overall survival was reported in the R-FC 
compared to the FC arm. 
 
Table 11 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 value 

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

Overall survival 51.9 NR 0.2874 17% 

Event free survival 19.3 28.7 0.0002 36% 

Response rate (CR, nPR, or PR) 
 
 
CR rates 
 
Duration of response * 
Disease free survival (DFS)** 
Time to new CLL treatment 

58.0% 
 
 

13.0% 
 

27.6 
42.2 
34.2 

69.9% 
 
 

24.3% 
 

39.6 
39.6 
NR 

0.0034 
 
 

0.0007 
 

0.0252 
0.8842 
0.0024 

n.a. 
 
 

n.a. 
 

31% 
-6% 
35% 

Response rate and CR rates analysed using Chi-squared Test. 
*: only applicable to patients achieving a CR, nPR, PR;   NR: not reached       n.a. not applicable 
**: only applicable to patients achieving a CR; 
 
Results from other supportive studies using 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. 
 



36 

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 rheumatoid arthritis 
 
The efficacy and safety of rituximab in alleviating the symptoms and signs of rheumatoid arthritis in 
patients with an inadequate response to TNF-inhibitors was demonstrated in a pivotal randomised, 
controlled, double-blind, multicenter trial (Trial 1). 
 
Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one or 
more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to 
the criteria of the American College of Rheumatology (ACR). Rituximab was administered as two 
intravenous infusions separated by an interval of 15 days. Patients received 2 x 1,000 mg intravenous 
infusions of rituximab or placebo in combination with MTX. All patients received concomitant 60 mg 
oral prednisone on days 2-7 and 30 mg on days 8-14 following the first infusion. The primary endpoint 
was the proportion of patients who achieved an ACR20 response at week 24. Patients were followed 
beyond week 24 for long term endpoints, including radiographic assessment at 56 weeks and at 
104 weeks. During this time, 81% of patients, from the original placebo group received rituximab 
between weeks 24 and 56, under an open label extension study protocol. 
 
Trials of rituximab in patients with early arthritis (patients without prior methotrexate treatment and 
patients with an inadequate response to methotrexate, but not yet treated with TNF-alpha inhibitors) 
have met their primary endpoints. Rituximab is not indicated for these patients, since the safety data 
about long-term rituximab treatment are insufficient, in particular concerning the risk of development 
of malignancies and PML. 
 
Disease activity outcomes 
Rituximab in combination with methotrexate significantly increased the proportion of patients 
achieving at least a 20% improvement in ACR score compared with patients treated with methotrexate 
alone (Table 12). Across all development studies the treatment benefit was similar in patients 
independent of age, gender, body surface area, race, number of prior treatments or disease status. 
 
Clinically and statistically significant improvement was also noted on all individual components of the 
ACR response (tender and swollen joint counts, patient and physician global assessment, disability 
index scores (HAQ), pain assessment and C-Reactive Proteins (mg/dL). 
 
Table 12 Clinical response outcomes at primary endpoint in Trial 1 (ITT population) 
 
 Outcome† Placebo+MTX Rituximab+MTX 

(2 x 1,000 mg) 

Trial 1  N=201 N=298 

 ACR20 
ACR50 
ACR70 

36 (18%) 
11 (5%) 
3 (1%) 

153 (51%)*** 
80 (27%)*** 
37 (12%)*** 

 EULAR response 
(good/moderate) 

44 (22%) 193 (65%)*** 

 Mean change in DAS -0.34 -1.83*** 

† Outcome at 24 weeks 
Significant difference from placebo + MTX at the primary timepoint: ***p ≤ 0.0001 
 



37 

Patients treated with rituximab in combination with methotrexate had a significantly greater reduction 
in disease activity score (DAS28) than patients treated with methotrexate alone (Table 12). Similarly, 
a good to moderate European League Against Rheumatism (EULAR) response was achieved by 
significantly more rituximab treated patients treated with rituximab and methotrexate compared to 
patients treated with methotrexate alone (Table 12). 
 
Radiographic response 
Structural joint damage was assessed radiographically and expressed as change in modified Total 
Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score. 
 
In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitor 
therapies, receiving rituximab in combination with methotrexate demonstrated significantly less 
radiographic progression than patients originally receiving methotrexate alone at 56 weeks. Of the 
patients originally receiving methotrexate alone, 81% received rituximab either as rescue between 
weeks 16-24 or in the extension trial, before week 56. A higher proportion of patients receiving the 
original rituximab/MTX treatment also had no erosive progression over 56 weeks (Table 13). 
 
Table 13 Radiographic outcomes at 1 year (mITT population) 
 
 Placebo+MTX Rituximab+MTX 

2 x 1,000 mg 

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

Modified total sharp score 2.30 1.01* 

Erosion score 1.32 0.60* 

Joint space narrowing score 0.98 0.41** 

Proportion of patients with no 
radiographic change 

46% 53%, NS 

Proportion of patients with no erosive 
change 

52% 60%, NS 

150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX by 
one year * p < 0.05, ** p < 0.001. Abbreviation: NS, non-significant 
 
Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis 
at 2 years in Trial 1 demonstrated significantly reduced progression of structural joint damage in 
patients receiving rituximab in combination with methotrexate compared to methotrexate alone as well 
as a significantly higher proportion of patients with no progression of joint damage over the 2 year 
period. 
 
Physical function and quality of life outcomes 
Significant reductions in disability index (HAQ-DI) and fatigue (FACIT-Fatigue) scores were 
observed in patients treated with rituximab compared to patients treated with methotrexate alone. The 
proportions of rituximab treated patients showing a minimal clinically important difference (MCID) in 
HAQ-DI (defined as an individual total score decrease of > 0.22) was also higher than among patients 
receiving methotrexate alone (Table 14). 
 
Significant improvement in health related quality of life was also demonstrated with significant 
improvement in both the physical health score (PHS) and mental health score (MHS) of the SF-36. 
Further, significantly higher proportion of patients achieved MCIDs for these scores (Table 14).  
 



38 

Table 14 Physical Function and Quality of Life outcomes at week 24 in Trial 1 
 

Outcome† Placebo+MTX Rituximab+MTX 
(2 x 1,000 mg) 

 
 
Mean change in HAQ-DI 

n=201 
 

0.1 

n=298 
 

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

n=197 
 

0.9 

n=294 
 

5.8*** 
% SF-36 PHS MCID 13% 48%*** 
Mean change in SF-36 MHS 1.3 4.7** 
% SF-36 MHS MCID 20% 38%* 

† Outcome at 24 weeks 
Significant difference from placebo at the primary time point: * p < 0.05, ** p < 0.001, *** p ≤ 0.0001 
MCID HAQ-DI ≥ 0.22, MCID SF-36 PHS > 5.42, MCID SF-36 MHS > 6.33 
 
Efficacy in autoantibody (RF and or anti-CCP) seropositive patients 
Patients seropositive to Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide (anti-CCP) 
who were treated with rituximab in combination with methotrexate showed an enhanced response 
compared to patients negative to both. 
 
Efficacy outcomes in rituximab treated patients were analysed based on autoantibody status prior to 
commencing treatment. At week 24, patients who were seropositive to RF and/or anti-CCP at baseline 
had a significantly increased probability of achieving ACR20 and 50 responses compared to 
seronegative patients (p=0.0312 and p=0.0096) (Table 15). These findings were replicated at week 48, 
where autoantibody seropositivity also significantly increased the probability of achieving ACR70. At 
week 48 seropositive patients were 2-3 times more likely to achieve ACR responses compared to 
seronegative patients. Seropositive patients also had a significantly greater decrease in DAS28-ESR 
compared to seronegative patients (Figure 1). 
 
Table 15 Summary of efficacy by baseline autoantibody status 
 
 Week 24 Week 48 
 Seropositive 

(n=514) 
Seronegative 

(n=106) 
Seropositive 

(n=506) 
Seronegative 

(n=101) 
ACR20 (%) 62.3* 50.9 71. 1* 51.5 
ACR50 (%) 32.7* 19.8 44.9** 22.8 
ACR70 (%) 12.1 5.7 20.9* 6.9 
EULAR response (%) 74.8* 62.9 84.3* 72.3 
Mean change DAS28-
ESR 

-1.97** -1.50 -2.48*** -1.72 

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



39 

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

 
 
Long-term efficacy with multiple course therapy 
Treatment with rituximab in combination with methotrexate over multiple courses resulted in 
sustained improvements in the clinical signs and symptoms of RA, as indicated by ACR, DAS28-ESR 
and EULAR responses which was evident in all patient populations studied (Figure 2). Sustained 
improvement in physical function as indicated by the HAQ-DI score and the proportion of patients 
achieving MCID for HAQ-DI were observed. 
 
Figure 2: ACR responses for 4 treatment courses (24 weeks after each course (within patient, 

within visit) in patients with an inadequate response to TNF-inhibitors (n=146) 

 
Clinical laboratory finding 
 
A total of 392/3,095 (12.7%) patients with rheumatoid arthritis tested positive for ADA in clinical 
studies following therapy with rituximab. The emergence of ADA was not associated with clinical 
deterioration or with an increased risk of reactions to subsequent infusions in the majority of patients. 



40 

The presence of ADA may be associated with worsening of infusion or allergic reactions after the 
second infusion of subsequent courses. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
rituximab in all subsets of the paediatric population with autoimmune arthritis. See section 4.2 for 
information on paediatric use. 
 
Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis 
 
Induction of remission 
A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis 
(75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator, 
randomised, double-blind, multicenter, non-inferiority trial. 
 
Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2 mg/kg/day) 
for 3-6 months or rituximab (375 mg/m2) once weekly for 4 weeks. All patients in the 
cyclophosphamide arm received azathioprine maintenance therapy in during follow-up. Patients in 
both arms received 1,000 mg of pulse intravenous methylprednisolone (or another equivalent-dose 
glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 
80 mg/day). Prednisone tapering was to be completed by 6 months from the start of trial treatment. 
 
The primary outcome measure was achievement of complete remission at 6 months defined as a 
Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off 
glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%. 
The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission (CR) 
at 6 months (Table 16). 
 
Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing 
disease (Table 17). 
 
Table 16 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. 

 



41 

Table 17 Complete remission at 6-months by disease status 
 
 Rituximab Cyclophosphamide Difference (CI 95%) 

All patients 
 
Newly diagnosed 
 
Relapsing 

n=99 
 

n=48 
 

n=51 

n=98 
 

n=48 
 

n=50 

 

Complete remission 
All patients 63.6% 53.1% 10.6% (-3.2, 24.3) 
Newly diagnosed 60.4% 64.6% -4.2% (-23.6, 15.3) 
Relapsing 66.7% 42.0% 24.7% (5.8, 43.6) 

Worst case imputation is applied for patients with missing data 
 
Complete remission at 12 and 18 months 
In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved CR 
at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of 
complete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at 
18 months. From month 12 to month 18, 8 relapses were observed in the rituximab group compared 
with four in the cyclophosphamide group. 
 
Laboratory evaluations 
A total of 23/99 (23%) rituximab-treated patients from the induction of remission trial tested positive 
for ADA by 18 months. None of the 99 rituximab-treated patients were ADA positive at screening. 
There was no apparent negative impact of the presence of ADA on safety or efficacy in the induction 
of remission trial. 
 
Maintenance treatment  
A total of 117 patients (88 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associated 
vasculitis) in disease remission were randomized to receive azathioprine (59 patients) or rituximab (58 
patients) in a prospective, multi-center, controlled, open-label study. Included patients were 21 to 75 
years of age and had newly diagnosed or relapsing disease in complete remission after combined 
treatment with glucocorticoids and pulse cyclophosphamide. The majority of patients were ANCA-
positive at diagnosis or during the course of their disease; had histologically confirmed necrotizing 
small-vessel vasculitis with a clinical phenotype of GPA/MPA, or renal limited ANCA-associated 
vasculitis; or both. 
 
Remission-induction therapy included IV prednisone, administered as per the investigator’s discretion, 
preceded in some patients by methylprednisolone pulses, and pulse cyclophosphamide until remission 
was attained after 4 to 6 months. At that time, and within a maximum of 1 month after the last 
cyclophosphamide pulse, patients were randomly assigned to receive either rituximab (two 500 mg IV 
infusions separated by two weeks (on Day 1 and Day 15) followed by 500 mg IV every 6 months for 
18 months) or azathioprine (administered orally at a dose of 2 mg/kg/day for 12 months, then 
1.5 mg/kg/day for 6 months, and finally 1 mg/kg/day for 4 months (treatment discontinuation after 
these 22 months)). Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg 
per day) for at least 18 months after randomization. Prednisone dose tapering and the decision to stop 
prednisone treatment after month 18 were left at the investigator’s discretion.  
 
All patients were followed until month 28 (10 or 6 months, respectively, after the last rituximab 
infusion or azathioprine dose). Pneumocystis jirovecii pneumonia prophylaxis was required for all 
patients with CD4+ T-lymphocyte counts less than 250 per cubic millimeter. 
 
The primary outcome measure was the rate of major relapse at month 28.  
 



42 

Results 
At month 28, major relapse (defined by the reappearance of clinical and/or laboratory signs of 
vasculitis activity ([BVAS] > 0) that could lead to organ failure or damage or could be life 
threatening) occurred in 3 patients (5%) in the rituximab group and 17 patients (29%) in the 
azathioprine group (p=0.0007). Minor relapses (not life threatening and not involving major organ 
damage) occurred in seven patients in the rituximab group (12%) and eight patients in the azathioprine 
group (14%).  
 
The cumulative incidence rate curves showed that time to first major relapse was longer in patients 
with rituximab starting from month 2 and was maintained up to month 28 (Figure 3). 
 
Figure 3:  Cumulative incidence over time of first major relapse 

      
 
 
Number of Subjects with Major Relapse 
Azathioprine 0 0 3 3 5 5 8 8 9 9 9 10 13 15 17 
Rituximab 0 0 0 0 1 1 1 1 1 1 1 1 3 3 3 
Number of subjects at risk 
Azathioprine 59 56 52 50 47 47 44 44 42 41 40 39 36 34 0 
Rituximab 58 56 56 56 55 54 54 54 54 54 54 54 52 50 0 
 
Note: Patients were censored at month 28 if they had no event.    
 
Laboratory evaluations 
A total of 6/34 (18%) of rituximab treated patients from the maintenance therapy clinical trial 
developed ADA. There was no apparent negative impact of the presence of ADA on safety or efficacy 
in the maintenance therapy clinical trial.  
 
Clinical experience in pemphigus vulgaris 
 
The efficacy and safety of rituximab in combination with short-term, low-dose glucocorticoid 
(prednisone) therapy were evaluated in newly diagnosed patients with moderate to severe pemphigus 
(74 pemphigus vulgaris [PV] and 16 pemphigus foliaceus [PF]) in this randomised, open-label, 
controlled, multicenter study. Patients were between 19 and 79 years of age and had not received prior 
therapies for pemphigus. In the PV population, 5 (13%) patients in the rituximab group and 3 (8%) 
patients in the standard prednisone group had moderate disease and 33 (87%) patients in the rituximab 
group and 33 (92%) patients in the standard-dose prednisone group had severe disease according to 
disease severity defined by Harman’s criteria. 

Survival Time (Months) 

Percent
age of 

Patients 
with 
First 

Major 
Relapse 



43 

 
Patients were stratified by baseline disease severity (moderate or severe) and randomised 1:1 to 
receive either rituximab and low-dose prednisone or standard-dose prednisone. Patients randomised to 
the rituximab group received an initial intravenous infusion of 1000 mg rituximab on Study Day 1 in 
combination with 0.5 mg/kg/day oral prednisone tapered off over 3 months if they had moderate 
disease or 1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease, and a 
second intravenous infusion of 1000 mg on Study Day 15. Maintenance infusions of rituximab 500 mg 
were administered at months 12 and 18. Patients randomised to the standard-dose prednisone group 
received an initial 1 mg/kg/day oral prednisone tapered off over 12 months if they had moderate 
disease or 1.5 mg/kg/day oral prednisone tapered off over 18 months if they had severe disease. 
Patients in the rituximab group who relapsed could receive an additional infusion of rituximab 
1000 mg in combination with reintroduced or escalated prednisone dose. Maintenance and relapse 
infusions were administered no sooner than 16 weeks following the previous infusion.  
 
The primary objective for the study was complete remission (complete epithelialisation and absence of 
new and/or established lesions) at month 24 without the use of prednisone therapy for two months or 
more (CRoff for ≥2 months).  
 
Results 
The study showed statistically significant results of rituximab and low-dose prednisone over standard-
dose prednisone in achieving CRoff ≥ 2 months at month 24 in PV patients (see Table 18).   
 
Table 18  Percentage of PV patients who achieved complete remission off corticosteroid 
therapy for two months or more at month 24 (Intent-to-Treat Population - PV) 

 Rituximab + 
Prednisone 
N=38 

Prednisone 
N=36 

 
p-value a 95% CIb 

Number of responders      
(response rate [%]) 

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

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

 

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

over time 

 
 



44 

Post-hoc retrospective laboratory evaluation 
A total of 19/34 (56%) patients with PV, who were treated with rituximab, tested positive for ADA 
antibodies by 18 months. The clinical relevance of ADA formation in rituximab-treated PV patients is 
unclear. 
 
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 to 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, 171-1,177 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). 
 
Rheumatoid arthritis 
 
Following two intravenous infusions of rituximab at a dose of 1,000 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 



45 

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 doses of 500 mg and 
1,000 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 1,000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 μg/mL for the 
2 x 500 mg dose and ranged from 355 to 404 μg/mL for the 2 x 1,000 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 1,000 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 intravenous doses of 500 mg and 
1,000 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 1,000 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 1,000 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 1,000 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 1,000 mg, intravenous, 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 – 49 days).  
Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 – 0.726 L/day) 
and 4.50 L (range 2.25 – 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 postnatally and was accompanied by a decrease 
in IgG level in the newborn animals affected. B cell counts returned to normal in these animals within 
6 months of birth and did not compromise the reaction to immunisation. 
 
Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant 
for this molecule. No long-term animal studies have been performed to establish the carcinogenic 
potential of rituximab.  
Specific studies to determine the effects of rituximab on fertility have not been performed. In general 
toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or 
females were observed. 
 
 



46 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium citrate 
Polysorbate 80 
Sodium chloride 
Sodium hydroxide 
Hydrochloric acid 
Water for injections 
 
6.2 Incompatibilities 
 
No incompatibilities between Rixathon and polyvinyl chloride or polyethylene bags or infusion sets 
have been observed. 
 
6.3 Shelf life 
 
Unopened vial 
3 years. 
 
Diluted solution 
• After aseptic dilution in sodium chloride solution: 
Chemical and physical stability of Rixathon diluted in 0.9% sodium chloride solution has been 
demonstrated for 30 days at 2°C - 8°C and subsequently 24 hours at room temperature (≤25°C). 
 
• After aseptic dilution in glucose solution: 
Chemical and physical stability of Rixathon diluted in 5% glucose solution has been demonstrated for 
24 hours at 2°C - 8°C and subsequently 12 hours at room temperature (≤25°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 
 
10 mL vial: Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 
10 mL. Packs of 2 or 3 vials. 
 
50 mL vial: Clear Type I glass vials with butyl rubber stopper containing 500 mg of rituximab in 
50 mL. Packs of 1 or 2 vials. 
 
6.6 Special precautions for disposal and other handling 
 
Rixathon is provided in sterile, preservative-free, non-pyrogenic, single use vials. 
 



47 

Aseptic preparation 
Aseptic handling must be ensured when preparing the infusion. Preparation should be: 
- performed under aseptic conditions by trained personnel in accordance with good practice rules 
especially with respect to the aseptic preparation of parenteral products. 
- prepared in a laminar flow hood or biological safety cabinet using standard precautions for the safe 
handling of intravenous agents. 
 
Aseptically withdraw the necessary amount of Rixathon, and dilute to a calculated concentration of 
1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 
9 mg/mL (0.9%) solution for injection or 5% D-Glucose in water. For mixing the solution, gently 
invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared 
solutions. Since the medicinal product does not contain any anti-microbial preservative or 
bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be 
inspected visually for particulate matter and discolouration prior to administration. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Rixathon 100 mg concentrate for solution for infusion 
EU/1/17/1185/001 
EU/1/17/1185/002 
 
Rixathon 500 mg concentrate for solution for infusion 
EU/1/17/1185/003 
EU/1/17/1185/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 15 June 2017 
 
 
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.  



48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) 
AND MANUFACTURER(S) 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 



49 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s)  
 
Sandoz GmbH Schaftenau 
Biochemiestr. 10 
6336 Langkampfen 
AUSTRIA 
 
Novartis Manufacturing GmbH 
Emil-von-Behring-Straße 76 
35041 Marburg 
Germany 
 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Sandoz GmbH Schaftenau 
Biochemiestr. 10 
6336 Langkampfen 
AUSTRIA 
 
Lek Pharmaceuticals d.d. Ljubljana 
Verovškova 57 
1526 Ljubljana 
Slovenia 
 
 
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 (PSUR)  
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

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

• At the request of the European Medicines Agency; 



50 

• 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 
 
For the indications non-Hodgkin´s lymphoma (NHL) and Chronic lymphocytic leukaemia 

(CLL): 
All physicians who are expected to prescribe Rixathon for NHL/CLL are provided with the following 
to reduce the risk of administration route errors: 
- Product information  
- HCP Alert card addressing the correct use of Rixathon 
 
The HCP Alert card addressing the correct use of Rixathon contains the following key elements: 
- The advice that Rixathon is for intravenous use only and recommendations how to ensure this 

route of administration 
 

For non-oncology indications: 
All physicians who are expected to prescribe Rixathon for non-oncology indications are provided with 
the following: 
- Product information  
- HCP educational leaflet 
- Patient educational leaflet 
A Patient Alert Card will be included in the carton. 
 
The HCP educational leaflet about Rixathon for non-oncology indications contains 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 Rixathon treatment, for infections, for immunosuppression, for 

prior/current medication affecting the immune system, and recent history of, or planned, 
vaccination, and a history of infusion-related reaction 

- The need to monitor patients for infections, especially PML, during and after Rixathon 
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 educational leaflet about Rixathon contains 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 Rixathon contains the following key elements: 
- The need to carry the card at all times and to show the card to all treating health care 

professionals 
- Warning on the risk of infections and PML, including the symptoms 
- The need for patients to contact their health care professional if symptoms occur 
 
The HCP educational leaflets and the Patient educational leaflet will be agreed with the National 
Competent Authorities prior to distribution. As the Patient Alert Card is part of the product 



51 

information in the outer packaging, the content will be centrally approved for all EU/EEA languages 
without need of further approval by National Authorities.  



52 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



53 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



54 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rixathon 100 mg concentrate for solution for infusion 
rituximab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 10 mg/mL rituximab. 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for 
injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
100 mg / 10 mL 
 
2 vials of 10 mL 
3 vials of 10 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Keep the container in the outer carton in order to protect from light. 



55 

 
 
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 
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1185/001 
EU/1/17/1185/002 
 
 
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 
 
 



56 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rixathon 100 mg sterile concentrate 
rituximab 
For intravenous use after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg / 10 mL 
 
 
6. OTHER 
 
 



57 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rixathon 500 mg concentrate for solution for infusion 
rituximab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial contains 10 mg/mL rituximab. 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for 
injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
500 mg / 50 mL 
 
1 vial of 50 mL 
2 vials of 50 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Keep the container in the outer carton in order to protect from light. 



58 

 
 
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 
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1185/003 
EU/1/17/1185/004 
 
 
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  
 
 



59 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Rixathon 500 mg sterile concentrate 
rituximab 
For intravenous use after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
500 mg / 50 mL 
 
 
6. OTHER 
 
 



60 

PATIENT ALERT CARD TEXT FOR NON-ONCOLOGY INDICATIONS 
 

Rixathon 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 
Rixathon 

• 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 Rixathon. 

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

When should I not have Rixathon? 

Do not have Rixathon 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:  
• Fever or persistent cough 
• 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 

Rixathon treatment. 

What else do I need to know? 

Rarely Rixathon 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 Rixathon treatment.  

Where can I get more information? 

See the Rixathon 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. 



61 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



62 

 
Package leaflet: Information for the patient 

 
Rixathon 100 mg concentrate for solution for infusion 
Rixathon 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 all of 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 Rixathon is and what it is used for 
2. What you need to know before you are given Rixathon 
3. How Rixathon is given 
4. Possible side effects 
5. How to store Rixathon 
6. Contents of the pack and other information 
 
 
1. What Rixathon is and what it is used for 
 
What Rixathon is 
Rixathon contains the active substance “rituximab”. This is a type of protein called a “monoclonal 
antibody”. It sticks to the surface of a type of white blood cell called “B-Lymphocyte”. When 
rituximab sticks to the surface of this cell, the cell dies. 
 
What Rixathon is used for 
Rixathon may be used for the treatment of several different conditions in adults. Your doctor may 
prescribe Rixathon for the treatment of: 
 
a) Non-Hodgkin’s Lymphoma 
This is a disease of the lymph tissue (part of the immune system) that affects a type of white blood cell 
called B-Lymphocytes. Rixathon can be given alone or with other medicines called “chemotherapy”. 
In patients where the treatment is working, Rixathon may be used as a maintenance treatment for 
2 years after completing the initial treatment. 
 
b) Chronic lymphocytic leukaemia 
Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL affects a 
particular lymphocyte, the B cell, which originates from the bone marrow and develops in the lymph 
nodes. Patients with CLL have too many abnormal lymphocytes, which accumulate mainly in the bone 
marrow and blood. The proliferation of these abnormal B-lymphocytes is the cause of symptoms you 
may have. Rixathon in combination with chemotherapy destroys these cells which are gradually 
removed from the body by biological processes. 
 
c) Rheumatoid arthritis 
Rixathon is used for the treatment of rheumatoid arthritis. Rheumatoid arthritis is a disease of the 
joints. B lymphocytes are involved in the cause of some of the symptoms you have. Rixathon is used 
to treat rheumatoid arthritis in people who have already tried some other medicines which have either 



63 

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

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

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

Rixathon 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 Rixathon. Your doctor may need to take special care of you during your treatment with 
Rixathon. 
 
If you have rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis or 
pemphigus vulgaris also tell your doctor 
• if you think you may have an infection, even a mild one like a cold. The cells that are affected 

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



64 

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

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

• 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 Rixathon. 
 
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 Rixathon can cross the placenta and may affect your 
baby. 
If you can get pregnant, you and your partner must use an effective method of contraception while 
using Rixathon. You must also do this for 12 months after your last treatment with Rixathon. Do not 
breast-feed while you are being treated with Rixathon. Also do not breast-feed for 12 months after 
your last treatment with Rixathon. This is because Rixathon may pass into breast milk. 
 
Driving and using machines 
Rituximab may make you feel dizzy and may affect your ability to drive or use any tools or machines. 
If you feel dizzy, do not drive or use any tools or machines. 
 
Rixathon contains sodium 
This medicine contains 2.3 mmol (or 52.6 mg) sodium per 10 mL vial. This medicine contains 11.5 
mmol (or 263.2 mg) sodium per 50 mL vial. To be taken into consideration by patients on a controlled 
sodium diet. 
 
 
3. How Rixathon is given 
 
How it is given 
Rixathon 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 Rixathon as a drip (intra-venous infusion). 
 
Medicines given before each Rixathon administration 
Before you are given Rixathon you will be given other medicines (premedication) to prevent or reduce 
possible side effects. 
 



65 

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

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

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

every 2 or 3 months for two years. Your doctor may change this, depending on how you 
respond to the medicine. 

 
b) If you are being treated for chronic lymphocytic leukaemia 
When you are treated with Rixathon in combination with chemotherapy, you will receive Rixathon 
infusions on day 0 cycle 1 then day 1 of each cycle for 6 cycles in total. Each cycle has a duration of 
28 days. The chemotherapy should be given after the Rixathon infusion. Your doctor will decide if 
you should receive concomitant supportive therapy. 
 
c) If you are being treated for rheumatoid arthritis 
Each course of treatment is made up of two separate infusions which are given 2 weeks apart. 
Repeated courses of treatment with Rixathon are possible. Depending on the signs and symptoms of 
your disease, your doctor will decide when you should receive more Rixathon. This may be months 
from now. 
 
d) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis 
Treatment with Rixathon uses four separate infusions given at weekly intervals. Corticosteroids will 
usually be given by injection before the start of Rixathon treatment. Corticosteroids given by mouth 
may be started at any time by your doctor to treat your condition. 
If you respond well to treatment, you may be given Rixathon as a maintenance treatment. This will be 
administered as 2 separate infusions which are given 2 weeks apart, followed by 1 infusion every 6 
months for at least 2 years. Your doctor may decide to treat you longer with Rixathon (up to 5 years), 
depending on how you respond to the medicine. 
 
e) If you are being treated for pemphigus vulgaris 
Each course of treatment is made up of two separate infusions which are given 2 weeks apart. If you 
respond well to treatment, you may be given Rixathon as a maintenance treatment. This will be 
administered 1 year and 18 months after the initial treatment and then every 6 months as needed or 
your doctor may change this, depending on how you respond to the medicine. 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Most side effects are mild to moderate but some may be serious and require treatment. Rarely, some of 
these reactions have been fatal. 
 
Infusion reactions 
During or within the first 24 hours of the infusion you may develop fever, chills and shivering. Less 
frequently, some patients may experience pain at the infusion site, blisters, itching, sickness (nausea), 
tiredness, headache, breathing difficulties, blood pressure raised, wheezing, throat discomfort, tongue 
or throat swelling, itchy or runny nose, vomiting, flushing or palpitations, heart attack or low number 
of platelets. If you have heart disease or angina, these reactions might get worse. Tell the person 
giving you the infusion immediately if you 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 



66 

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 
Rixathon 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 Rixathon.  
These are often colds, but there have been cases of pneumonia or urinary infections. These are listed 
below under “Other side effects”.  
 
If you are being treated for rheumatoid arthritis, granulomatosis with polyangiitis, microscopic 
polyangiitis or pemphigus vulgaris, you will also find this information in the Patient Alert Card you 
have been given by your doctor. It is important that you keep this Alert Card and show it to your 
partner or caregiver. 
 
Skin reactions 
Very rarely, severe blistering skin conditions that can be life-threatening may occur. Redness, often 
associated with blisters, may appear on the skin or on mucous membranes, such as inside the mouth, 
the genital areas or the eyelids, and fever may be present. Tell your doctor immediately if you 
experience any of these symptoms. 
 
Other side effects include: 
a) If you are being treated for non-Hodgkin’s Lymphoma or chronic lymphocytic leukaemia 
 
Very common side effects (may affect more than 1 in 10 people): 
• bacterial or viral infections, bronchitis 
• low number of white blood cells, with or without fever or blood cells called “platelets” 
• feeling sick (nausea) 
• bald spots on the scalp, chills, headache 
• lower immunity – because of lower levels of anti-bodies called “immunoglobulins” (IgG) in the 

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

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

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

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

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

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



67 

• 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 rheumatoid arthritis 

 
Very common side effects (may affect more than 1 in 10 people): 
• Infections such as pneumonia (bacterial) 
• Pain on passing water (urinary tract infection) 
• Allergic reactions that are most likely to occur during an infusion, but can occur up-to 24-hours 

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

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

of some specific proteins in the blood (immunoglobulins) which help protect against infection. 
 
Common side effects (may affect up to 1 in 10 people): 
• Infections such as bronchial tube inflammation (bronchitis) 
• A feeling of fullness or a throbbing pain behind the nose, cheeks and eyes (sinusitis), pain in the 

abdomen, vomiting and diarrhoea, breathing problems 



68 

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

migraine, dizziness 
• Loss of hair 
• Anxiety, depression 
• Indigestion, diarrhoea, acid reflux, irritation and /or ulceration of the throat and the mouth 
• Pain in the tummy, back, muscles and/or joints 
 
Uncommon side effects (may affect up to 1 in 100 people): 
• Excess fluid retention in the face and body 
• Inflammation, irritation and / or tightness of the lungs, and throat, coughing 
• Skin reactions including hives, itching and rash 
• Allergic reactions including wheezing or shortness of breath, swelling of the face and tongue, 

collapse 
 
Very rare side effects (may affect up to 1 in 10,000 people): 
• A complex of symptoms occurring within a few weeks of an infusion of rituximab including 

allergic like reactions such as rash, itching, joint pain, swollen lymph glands and fever 
• Severe blistering skin conditions that can be life-threatening. Redness, often associated with 

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

 
Other rarely-reported side-effects due to rituximab include a decreased number of white cells in the 
blood (neutrophils) that help to fight against infection. Some infections may be severe (please see 
information on Infections within this section). 
 
c) 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) 
• difficulty sleeping (insomnia) 
• swelling of the hands or ankles 
 
Common side effects (may affect up to 1 in 10 people): 
• indigestion 
• constipation 
• skin rashes, including acne or spots 
• flushing or redness of the skin 
• fever 
• blocked or runny nose 
• tight or painful muscles 
• pain in the muscles or in the hands or feet 
• low number of red blood cells (anaemia) 



69 

• 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  
 
d) If you are being treated for pemphigus vulgaris 
 
Very common side effects (may affect more than 1 in 10 people): 
• allergic reactions that are most likely to occur during an infusion, but can occur up to 24 hours 

after infusion 
• long lasting depression 
• loss of hair 
 
Common side effects (may affect up to 1 in 10 people): 
• infections such as herpes infections and eye infection 
• mood disorders such as irritability and depression 
• skin disorders such as itching, hives, and benign lumps 
• feeling tired or dizzy 
• fever 
• headache 
• pain in the tummy 
• pain in the muscles 
• heart beating faster than normal 
 
Rixathon may also cause changes in laboratory tests carried out by your doctor. 
If you are having Rixathon with other medicines, some of the side effects you may get may be due to 
the other medicines. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Rixathon 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). 
Keep the container in the outer carton in order to protect from light. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines that you no longer use. These measures will help protect the environment. 
 
 



70 

6. Contents of the pack and other information 
 
What Rixathon contains 
 
• The active ingredient in Rixathon is called rituximab.  

The 10 mL vial contains 100 mg of rituximab (10 mg/mL). 
The 50 mL vial contains 500 mg of rituximab (10 mg/mL). 
 

• The other ingredients are sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, 
hydrochloric acid and water for injections (see section 2). 

 
What Rixathon looks like and contents of the pack 
 
Rixathon is a clear, colourless to slightly yellowish solution, supplied as a concentrate for solution for 
infusion. 
10 mL vial - Pack of 2 or 3 vials.  
50 mL vial - Pack of 1 or 2 vials. 
 
Marketing Authorisation Holder 
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
Manufacturer 
 
Sandoz GmbH Schaftenau 
Biochemiestr. 10 
6336 Langkampfen 
Austria 
 
Lek Pharmaceuticals d.d. Ljubljana 
Verovškova 57 
1526 Ljubljana 
Slovenia 
 
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. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) 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