Ruxience

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Ruxience 100 mg concentrate for solution for infusion
Ruxience 500 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Ruxience 100 mg concentrate for solution for infusion

Each mL contains 10 mg of rituximab. 
Each 10 mL vial contains 100 mg of rituximab.

Ruxience 500 mg concentrate for solution for infusion

Each mL contains 10 mg of rituximab. 
Each 50 mL vial contains 500 mg of rituximab.

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a 
glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and
heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster
ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including
specific viral inactivation and removal procedures.

Excipient with known effect
This medicinal product contains less than 1 mmol sodium (23 mg) per dose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 

Concentrate for solution for infusion (sterile concentrate). 

Clear to slightly opalescent, colourless to pale brownish-yellow liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Ruxience is indicated in adults for the following indications: 

Non-Hodgkin’s lymphoma (NHL)

Ruxience is indicated for the treatment of previously untreated patients with stage III-IV follicular 
lymphoma in combination with chemotherapy.

Ruxience maintenance therapy is indicated for the treatment of follicular lymphoma patients 
responding to induction therapy.



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Ruxience 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.

Ruxience 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)

Ruxience in combination with chemotherapy is indicated for the treatment of patients with previously 
untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for 
patients previously treated with monoclonal antibodies including rituximab or patients refractory to 
previous rituximab plus chemotherapy.

See section 5.1 for further information. 

Rheumatoid arthritis

Ruxience 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.

Ruxience 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

Ruxience, 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 

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

4.2 Posology and method of administration

Ruxience 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 Ruxience.

In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be 
considered if Ruxience 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 Ruxience to decrease the 
rate and severity of acute infusion reactions and/or cytokine release syndrome.



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In patients with rheumatoid arthritis, granulomatosis with polyangiitis (Wegener’s) or microscopic
polyangiitis in disease remission or pemphigus vulgaris, premedication with 100 mg intravenous 
methylprednisolone should be completed 30 minutes prior to Ruxience 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 1000 mg per day is recommended 
prior to the first infusion of Ruxience (the last dose of methylprednisolone may be given on the same 
day as the first infusion of Ruxience). 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 Ruxience treatment.

Pneumocystis jirovecii pneumonia (PCP) prophylaxis is recommended for patients with GPA/MPA or 
PV during and following Ruxience 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 Ruxience 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.

Ruxience 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 Ruxience 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 Ruxience 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 Ruxience 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 re-treatment with Ruxience 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).



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Diffuse large B cell non-Hodgkin's lymphoma

Ruxience 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 Ruxience are recommended. When Ruxience is given in combination with 
chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be 
applied.

Chronic lymphocytic leukaemia

The recommended dosage of Ruxience 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 Ruxience infusion.

Rheumatoid arthritis

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

A course of Ruxience consists of two 1000 mg intravenous infusions. The recommended dosage of 
Ruxience is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two 
weeks later.

The need for further courses should be evaluated 24 weeks following the previous course. 
Re-treatment should be given at that time if residual disease activity remains, otherwise re-treatment 
should be delayed until disease activity returns.

Available data suggest that clinical response is usually achieved within 16 - 24 weeks of an initial 
treatment course. Continued therapy should be carefully reconsidered in patients who show no 
evidence of therapeutic benefit within this time period.

Granulomatosis with polyangiitis and microscopic polyangiitis

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

Induction of remission
The recommended dosage of Ruxience 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 Ruxience, maintenance treatment should be initiated no sooner 
than 16 weeks after the last Ruxience infusion.

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

Ruxience 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 Ruxience for at least 24 months 
after achievement of remission (absence of clinical signs and symptoms). For patients who may be at 



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higher risk for relapse, physicians should consider a longer duration of Ruxience maintenance therapy, 
up to 5 years.

Pemphigus vulgaris

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

The recommended dosage of Ruxience 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 has not been established. No data are 
available.

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

Method of administration

The prepared Ruxience 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) (see 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/hour; after the first 30 minutes, it can be escalated 
in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.



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Subsequent infusions

All indications

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

Rheumatoid arthritis only

Alternative subsequent, faster, infusion schedule

If patients did not experience a serious infusion-related reaction with their first or subsequent infusions 
of a dose of 1000 mg Ruxience 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

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

Progressive multifocal leukoencephalopathy

All patients treated with Ruxience for rheumatoid arthritis, granulomatosis with polyangiitis,
microscopic polyangiitis or pemphigus vulgaris must be given the patient alert card with each infusion. 
The alert card contains important safety information for patients regarding potential increased risk of 
infections, including progressive multifocal leukoencephalopathy (PML).



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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 Ruxience must be permanently discontinued. 

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

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Infusion-related reactions
Rituximab is associated with infusion-related reactions, which may be related to release of cytokines 
and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from 
acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and 
anaphylactic and hypersensitivity reactions are described below. 

Severe infusion-related reactions with fatal outcome have been reported during post-marketing use of 
the rituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours after 
starting the first rituximab intravenous infusion. They were characterised by pulmonary events and in 
some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, 
chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by 
bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This 
syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, 
hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate 
dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute 
respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, 
visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating 
the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour 
infiltration may be at greater risk of poor outcome and should be treated with increased caution.
Patients who develop severe cytokine release syndrome should have their infusion interrupted 
immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial 
improvement of clinical symptoms may be followed by deterioration, these patients should be closely 
monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out.
Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in 
repeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (≥ 25 x 109/L) of circulating malignant cells 
such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome,
should be treated with extreme caution. These patients should be very closely monitored throughout 



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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 products for 12 hours prior to the Ruxience 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 
Ruxience therapy.

Infections
Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8). 
Ruxience 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 Ruxience in patients with a history of 
recurring or chronic infections or with underlying conditions which may further predispose patients to 
serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in subjects receiving rituximab including 
fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic 
chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that 
rituximab treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus 
(HBV) screening should be performed in all patients before initiation of treatment with Ruxience. 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



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treated with Ruxience. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should 
consult liver disease experts before start of treatment and should be monitored and managed following 
local medical standards to prevent hepatitis B reactivation.

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

Immunisations
The safety of immunisation with live viral vaccines, following rituximab therapy has not been studied 
for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients
treated with Ruxience 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 titre). For CLL patients 
similar results are assumable considering similarities between both diseases but that has not been 
investigated in clinical trials.

Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza 
A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with rituximab.

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

Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis, 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 Ruxience. In most cases, the infusion can be 
resumed at a 50% reduction in rate (e.g. from 100 mg/hour to 50 mg/h) when symptoms have 
completely resolved.

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



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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 Ruxience
and patients closely monitored during administration. Since hypotension may occur during rituximab
infusion, consideration should be given to withholding anti-hypertensive medicinal products for 
12 hours prior to the Ruxience infusion.

IRRs for patients with granulomatosis with polyangiitis, microscopic polyangiitis and pemphigus
vulgaris were consistent with 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). Ruxience 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 Ruxience.

Patients reporting signs and symptoms of infection following Ruxience therapy should be promptly 
evaluated and treated appropriately. Before giving a subsequent course of Ruxience 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 Ruxience. At minimum this should include HBsAg-status and HBcAb-status. These can be 
complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B 
disease should not be treated with rituximab. Patients with positive hepatitis B serology (either HBsAg 
or HBcAb) should consult liver disease experts before start of treatment and should be monitored and 
managed following local medical standards to prevent hepatitis B reactivation.

Late neutropenia
Measure blood neutrophils prior to each course of Ruxience, and regularly up to 6-months after 
cessation of treatment, and upon signs or symptoms of infection (see section 4.8).



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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 Ruxience, treatment should be permanently discontinued.

Immunisation
Physicians should review the patient’s vaccination status and follow current immunisation guidelines 
prior to Ruxience therapy. Vaccination should be completed at least 4 weeks prior to first 
administration of Ruxience.

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 Ruxience or whilst 
peripherally B cell depleted.

Patients treated with Ruxience 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 Ruxience 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 drugs 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.

Excipient: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say 
essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in 
rheumatoid arthritis patients.



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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 Ruxience.

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 Ruxience 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 Ruxience and for 12 months following Ruxience treatment.

Fertility

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

4.7 Effects on ability to drive and use machines

No studies on the effects of rituximab on the ability to drive and use machines have been performed, 
although the pharmacological activity and adverse reactions reported to date suggest that rituximab
would have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

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 CLL is based on data from 
patients from clinical trials and from post-marketing surveillance. These patients were treated either 
with rituximab monotherapy (as induction treatment or maintenance treatment following induction 
treatment) or in combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab were 
IRRs which occurred in the majority of patients during the first infusion. The incidence of



14

infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after 
eight doses of rituximab.

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

The most frequent reported or observed serious adverse drug reactions were:
 IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.
 Infections, see section 4.4.
 Cardiovascular events, see section 4.4.

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

Tabulated list of adverse reactions

The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy are 
summarised in Table 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), very rare (< 1/10,000) and 
not known (cannot be estimated from the available data).

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

Table 1 ADRs reported in clinical trials or during post-marketing surveillance in patients 
with NHL and CLL disease treated with rituximab monotherapy/maintenance or in 
combination with chemotherapy

System Organ 
Class

Very Common Common Uncommon Rare Very Rare Not Known

Infections and 
infestations

bacterial 
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, 
Pneumocysti
s jirovecii

PML

Blood and 
lymphatic 
system 
disorders

neutropenia, 
leucopenia, 
+febrile 
neutropenia, 
+thrombocytopen
ia

anaemia, 
+pancytopenia, 
+granulocytopeni
a

coagulation 
disorders, 
aplastic 
anaemia, 
haemolytic 
anaemia, 
lymphadenopat
hy

transient 
increase in 
serum IgM 
levels3

late neutropenia3

Immune 
system 
disorders

infusion-related 
reactions4, 
angioedema

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

infusion-related 
acute reversible 
thrombocytopeni
a4



15

System Organ 
Class

Very Common Common Uncommon Rare Very Rare Not Known

Metabolism 
and nutrition 
disorders

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

Psychiatric 
disorders

depression, 
nervousness

Nervous 
system 
disorders

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

dysgeusia peripheral 
neuropathy, 
facial nerve 
palsy5

cranial 
neuropathy, loss 
of other senses5

Eye disorders lacrimation 
disorder, 
conjunctivitis

severe vision 
loss5

Ear and 
labyrinth 
disorders

tinnitus, ear pain hearing loss5

Cardiac 
disorders

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

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

severe 
cardiac 
disorders 4 
and 6

heart failure4 
and 6

Vascular 
disorders

hypertension, 
orthostatic 
hypotension, 
hypotension

vasculitis 
(predominatel
y cutaneous), 
leukocytoclasti
c vasculitis

Respiratory,
thoracic and 
mediastinal 
disorders

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

asthma, 
bronchiolitis 
obliterans, lung 
disorder, 
hypoxia

interstitial 
lung disease7

respiratory 
failure4

lung infiltration

Gastrointestina
l disorders

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

abdominal 
enlargement

gastro-
intestinal 
perforation7

Skin and 
subcutaneous 
tissue disorders

pruritus, rash, 
+alopecia

urticaria, 
sweating, night 
sweats, +skin 
disorder

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

Musculoskeleta
l, connective 
tissue and bone 
disorders

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



16

System Organ 
Class

Very Common Common Uncommon Rare Very Rare Not Known

Renal and 
urinary 
disorders

renal failure4

General 
disorders and 
administration 
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 
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



17

(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 re-treatment 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 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 



18

grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the 
relapsed/refractory study (4% R-FC, 4% FC).

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

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

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

Gastrointestinal disorders
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving 
rituximab for treatment of non-Hodgkin lymphoma. In the majority of these cases, rituximab was 
administered with chemotherapy.

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

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

Skin and subcutaneous tissue disorders
Toxic Epidermal Necrolysis (Lyell syndrome) and Stevens-Johnson syndrome, some with fatal 
outcome, have been reported very rarely.

Patient subpopulations - rituximab monotherapy
Elderly patients (≥ 65 years):
The incidence of ADRs of all grades and grade 3/4 ADR was similar in elderly patients compared to 
younger patients (< 65 years).

Bulky disease
There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients without 
bulky disease (25.6% vs. 15.4%). The incidence of ADRs of any grade was similar in these two 
groups.



19

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 3100 patients received at least one 
treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 
2400 patients received two or more courses of treatment with over 1000 having received 5 or more 
courses. The safety information collected during post-marketing experience reflects the expected 
adverse reaction profile as seen in clinical trials for rituximab (see section 4.4).

Patients received 2 x 1000 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), rare (≥ 1/10,000 to < 1/1,000), and very rare
(< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness.

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

Table 2 Summary of adverse drug reactions reported in clinical trials or during 
post-marketing surveillance occurring in patients with rheumatoid arthritis receiving 
rituximab

System Organ 
Class

Very Common Common Uncommon Rare Very Rare

Infections and 
infestations

upper respiratory 
tract infection, 
urinary tract 
infections

bronchitis, sinusitis, 
gastroenteritis, tinea 
pedis

PML, 
reactivation of 
hepatitis B

Blood and 
lymphatic 
system disorders

neutropenia1 late neutropenia2 serum 
sickness-like 
reaction

Cardiac 
disorders

angina pectoris, 
atrial fibrillation, 
heart failure, 
myocardial 
infarction

atrial flutter



20

System Organ 
Class

Very Common Common Uncommon Rare Very Rare

Immune system 
disorders

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

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

General 
disorders and 
administration 
site conditions

Metabolism and 
nutritional 
disorders

hypercholesterolemia

Nervous system 
disorders

headache paraesthesia, 
migraine, dizziness, 
sciatica

Skin and 
subcutaneous 
tissue disorders

alopecia Toxic Epidermal 
Necrolysis 
(Lyell’s 
syndrome), 
Stevens-Johnson 
syndrome5

Psychiatric 
disorders

depression, anxiety

Gastrointestinal 
disorders

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

Musculoskeletal 
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, 1135 (36%) experienced at least one IRR with 
733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to 
rituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1% 
(17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due 



21

to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal 
decreased by course and were rare from course 3 onwards. Premedication with intravenous 
glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4).
Severe IRRs with fatal outcome have been reported in the post-marketing setting.

In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with rheumatoid 
arthritis, patients with moderate-to-severe active RA who did not experience a serious IRR during or 
within 24 hours of their first studied infusion were allowed to receive a 2-hour intravenous infusion of 
rituximab. Patients with a history of a serious infusion reaction to a biologic therapy for RA were 
excluded from entry. The incidence, types and severity of IRRs were consistent with that observed 
historically. No serious IRRs were observed.

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

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

In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic 
chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma). 
Reactivation of hepatitis B infection has also been very rarely reported in rheumatoid arthritis patients 
receiving rituximab (see section 4.4).

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

Neurologic events
Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior 
leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual 
disturbance, headache, seizures and altered mental status, with or without associated hypertension. A 
diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised 
risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, 
immunosuppressive therapy and/or chemotherapy.

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

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and 
0.27% (2/731) of placebo 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.



22

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

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

Experience from granulomatosis with polyangiitis 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 reactions 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.

System Organ Class
Adverse reactions

Rituximab
(n=99)

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

Blood and lymphatic system disorders
Thrombocytopenia 7%

Immune system disorders
Cytokine release syndrome 5%

Metabolism and nutrition disorders
Hyperkalaemia 5%

Psychiatric disorders
Insomnia 14%

Nervous system disorders
Dizziness 10%
Tremor 10%

Vascular disorders
Hypertension 12%
Flushing 5%

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

Gastrointestinal disorders
Diarrhoea 18%
Dyspepsia 6%
Constipation 5%

Skin and subcutaneous tissue disorders
Acne 7%



23

System Organ Class
Adverse reactions

Rituximab
(n=99)

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

General disorders and administration site conditions
Peripheral oedema 16%

Investigations
Decreased haemoglobin 6%

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.

2 Details on infusion-related reactions are provided in the description of selected adverse drug reactions section.

The overall safety profile was consistent with the well-established safety profile for rituximab in 
approved autoimmune indications, including GPA/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.



24

Description of selected adverse drug reactions

Infusion-related reactions
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 99 patients treated with rituximab, 12 
(12%) experienced at least one IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs 
included cytokine release syndrome, flushing, throat irritation, and tremor. Rituximab was given in 
combination with intravenous glucocorticoids which may reduce the incidence and severity of these 
events.

In 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 
post-marketing setting.



25

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, 
multicentre, 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)

Infections and infestations

Herpes virus infection 8%



26

Herpes zoster 5%

Oral herpes 5%

Conjunctivitis 5%

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Skin papilloma 5%

Psychiatric disorders

Persistent depressive disorder 13%

Major depression 5%

Irritability 5%

Nervous system disorders

Headache 5%

Dizziness 5%

Cardiac disorders

Tachycardia 5%

Gastrointestinal disorders

Abdominal pain upper 5%

Skin and subcutaneous tissue disorders

Alopecia 13%

Pruritus 5%

Urticaria 5%

Skin disorder 5%

Musculoskeletal and connective tissue disorders

Musculoskeletal pain 5%

General disorders and administration site conditions

Fatigue 8%

Pyrexia 5%

Injury, poisoning and procedural complications

Infusion-related reactions* 58%

* 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. 



27

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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V.

4.9 Overdose

Limited experience with doses higher than the approved dose of intravenous rituximab formulation is 
available from clinical trials in humans. The highest intravenous dose of rituximab tested in humans to 
date is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. No additional 
safety signals were identified.

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

In the post-marketing setting five cases of rituximab overdose have been reported. Three cases had no 
reported adverse event. The two adverse events that were reported were flu-like symptoms, with a dose 
of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02 

Ruxience 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 Fc receptors on the 
surface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on B 
lymphocytes has also been demonstrated to induce cell death via apoptosis.



28

Peripheral B cell counts declined below normal following completion of the first dose of rituximab. In 
patients treated for haematological malignancies, B cell recovery began within 6 months of treatment 
and generally returned to normal levels within 12 months after completion of therapy, although in 
some patients this may take longer (up to a median recovery time of 23 months post-induction 
therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was 
observed following two infusions of 1000 mg rituximab separated by a 14 day interval. Peripheral 
blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the 
majority of patients by week 40, whether rituximab was administered as monotherapy or in 
combination with methotrexate. A small proportion of patients had prolonged peripheral B cell 
depletion lasting 2 years or more after their last dose of rituximab. In patients with granulomatosis 
with polyangiitis or microscopic polyangiitis, the number of peripheral blood B cells decreased to 
< 10 cells/μL after two weekly infusions of rituximab 375 mg/m2, and remained at that level in most
patients up to the 6 month timepoint. The majority of patients (81%) showed signs of B cell return, 
with counts > 10 cells/μL by month 12, increasing to 87% of patients by month 18.

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

Follicular lymphoma

Monotherapy

Initial treatment, weekly for 4 doses
In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL 
received 375 mg/m2 of 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 multicentre, single-arm trial, 37 patients with relapsed or chemoresistant, low-grade or follicular B 
cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for eight doses. The ORR 
was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a projected median 
TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).

Initial treatment, bulky disease, weekly for 4 doses
In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (single 
lesion ≥ 10 cm in diameter), low-grade or follicular B cell NHL received 375 mg/m2 of rituximab as 
intravenous infusion weekly for four doses. The ORR was 36% (CI95% 21% – 51%; CR 3%, PR 33%) 
with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

Re-treatment, weekly for 4 doses
In a 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



29

patients had received two courses of rituximab before enrolment and thus were given a third course in 
the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORR 
was 38% (CI95% 26% – 51%; 10% CR, 28% PR) with a projected median TTP for responding patients 
of 17.8 months (range 5.4 – 26.6). This compares favourably with the TTP achieved after the prior 
course of rituximab (12.4 months).

Initial treatment, in combination with chemotherapy

In an open-label randomised trial, a total of 322 previously untreated patients with follicular 
lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2, 
vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1 
5) every 3 weeks for 8 cycles or rituximab 375 mg/m2 in combination with CVP (R-CVP). Rituximab
was administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP, 159 
CVP) received therapy and were analysed for efficacy. The median follow-up of patients was 
53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment 
failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour 
response (CR, CRu, PR) was significantly higher (p < 0.0001 Chi-Square test) in the R-CVP group 
(80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to 
disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively
(p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and 
was 13.5 months in the CVP group (p < 0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significant 
clinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were 80.9% 
for patients in the R-CVP group compared to 71.1% for patients in the CVP group.

Results from three other randomised trials using rituximab in combination with chemotherapy regimen 
other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant improvements
in response rates, time-dependent parameters as well as in overall survival. Key results from all four 
studies are summarised in Table 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
months

OS
rates,
%

M39021
CVP, 159
R-CVP, 162

53
57
81

10
41

Median TTP:
14.7
33.6

p < 0.0001

53-months
71.1
80.9

p = 0.029

GLSG’00
CHOP, 205
R-CHOP, 223

18
90
96

17
20

Median TTF: 
2.6 years

Not reached
p < 0.001

18-months
90
95

p = 0.016

OSHO-39
MCP, 96
R-MCP, 105

47
75
92

25
50

Median PFS: 28.8
Not reached
p < 0.0001

48-months
74
87

p = 0.0096

FL2000

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

42
85
94

49
76

Median EFS: 36
Not reached
p < 0.0001

42-months 
84
91

p = 0.029
EFS – Event Free Survival
TTP – Time to progression or death 
PFS – Progression-Free Survival 
TTF – Time to Treatment Failure
OS rates – survival rates at the time of the analyses



30

Maintenance therapy

Previously untreated follicular lymphoma
In a prospective, open label, international, multi-centre, phase III trial 1193 patients with previously 
untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP 
(n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1078 patients responded 
to induction therapy, of which 1018 were randomised to rituximab maintenance therapy (n=505) or 
observation (n=513). The two treatment groups were well balanced with regards to baseline 
characteristics and disease status. Rituximab maintenance treatment consisted of a single infusion of
rituximab at 375 mg/m2 body surface area given every 2 months until disease progression or for a 
maximum period of two years.

The pre-specified primary analysis was conducted at a median observation time of 25 months from 
randomisation, maintenance therapy with rituximab resulted in a clinically relevant and statistically 
significant improvement in the primary endpoint of investigator assessed progression-free survival 
(PFS) as compared to observation in patients with previously untreated follicular lymphoma (Table 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     Rituximab
N=513 N=505

Observation     Rituximab
N=513 N=505

Primary efficacy
Progression-free survival (median) NR NR 4.06 years 10.49 years
log-rank p value <0.0001 <0.0001
hazard ratio (95% CI) 0.50 (0.39, 0.64) 0.61 (0.52, 0.73)
risk reduction 50% 39%
Secondary efficacy
Overall survival (median) NR NR NR NR
log-rank p value 0.7246 0.7948
hazard ratio (95% CI) 0.89 (0.45, 1.74) 1.04 (0.77, 1.40)
risk reduction 11% -6%
Event-free survival (median) 38 months NR 4.04 years 9.25 years
log-rank p value <0.0001 <0.0001
hazard ratio (95% CI) 0.54 (0.43, 0.69) 0.64 (0.54, 0.76)
risk reduction 46% 36%
TNLT (median) NR NR 6.11 years NR
log-rank p value 0.0003 <0.0001
hazard ratio (95% CI) 0.61 (0.46, 0.80) 0.66 (0.55, 0.78)
risk reduction 39% 34%
TNCT (median) NR NR 9.32 years NR
log-rank p value 0.0011 0.0004
hazard ratio (95% CI) 0.60 (0.44, 0.82) 0.71 (0.59, 0.86)
risk reduction 40% 39%
Overall response rate* 55% 74% 61% 79%
chi-squared test p value <0.0001 <0.0001
odds ratio (95% CI) 2.33 (1.73, 3.15) 2.43 (1.84, 3.22)



31

Primary analysis
(median FU: 25 months)

Final analysis
(median FU: 9.0 years)

Observation     Rituximab
N=513 N=505

Observation     Rituximab
N=513 N=505

Complete response (CR/CRu) rate* 48% 67% 53% 67%
chi-squared test p value <0.0001 <0.0001
odds ratio (95% CI) 2.21 (1.65, 2.94) 2.34 (1.80, 3.03)
* at end of maintenance/observation; final analysis result s 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.

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) 74% 87% 0.0003 Na

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

1) Estimates were calculated by hazard ratios
2) Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of 
CR versus PR versus non-response (p < 0.0001)
Abbreviations: NA, not available; ORR: overall response rate; CR: complete response; PR: partial response

For patients randomised to the maintenance phase of the trial, the median observation time was 
28 months from maintenance randomisation. Maintenance treatment with rituximab led to a clinically 
relevant and statistically significant improvement in the primary endpoint, PFS, (time from 
maintenance randomisation to relapse, disease progression or death) when compared to observation 
alone (p < 0.0001 log-rank test).The median PFS was 42.2 months in the rituximab maintenance arm 
compared to 14.3 months in the observation arm. Using a cox regression analysis, the risk of 
experiencing progressive disease or death was reduced by 61% with rituximab maintenance treatment 
when compared to observation (95% CI; 45%-72%). Kaplan-Meier estimated progression-free rates at 
12 months were 78% in the rituximab maintenance group vs. 57% in the 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%).



32

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%

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

CHOP 11.6 37.5 < 0.0001 71%
R-CHOP 22.1 51.9 0.0071 46%

CR 14.3 52.8 0.0008 64%
PR 14.3 37.8 < 0.0001 54%

OS
CHOP NR NR 0.0348 55%

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

The benefit of rituximab maintenance treatment was confirmed in all subgroups analysed, regardless 
of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR)
(Table 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



33

complete response rate after cycle 8 was 76.2% in the R-CHOP group and 62.4% in the CHOP group 
(p=0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by 51%. In all 
patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2 microglobulin, LDH, 
albumin, B symptoms, bulky disease, extranodal sites, bone marrow involvement), the risk ratios for 
event-free survival and overall survival (R-CHOP compared with CHOP) were less than 0.83 and 0.95 
respectively. R-CHOP was associated with improvements in outcome for both high- and low-risk 
patients according to age adjusted IPI.

Clinical laboratory findings

Of 67 patients evaluated for 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



34

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.

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 CLL. See section
4.2 for information on paediatric use.



35

Clinical experience in rheumatoid arthritis

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

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one or 
more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to 
the criteria of the American College of Rheumatology (ACR). Rituximab was administered as two IV 
infusions separated by an interval of 15 days. Patients received 2 x 1000 mg intravenous infusions of 
rituximab or placebo in combination with MTX. All patients received concomitant 60 mg oral 
prednisone on days 2-7 and 30 mg on days 8-14 following the first infusion. The primary endpoint was 
the proportion of patients who achieved an ACR20 response at week 24. Patients were followed 
beyond week 24 for long-term endpoints, including radiographic assessment at 56 weeks and at 104 
weeks. During this time, 81% of patients, from the original placebo group received rituximab between 
weeks 24 and 56, under an open label extension study protocol.

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

Disease activity outcomes
Rituximab in combination with methotrexate significantly increased the proportion of patients 
achieving at least a 20% improvement in ACR score compared with patients treated with methotrexate 
alone (Table 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 1000 mg)
Trial 1 N=201 N=298

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

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

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

EULAR Response
(Good/Moderate)

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

Mean Change in DAS -0.34 -1.83***

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

Patients treated with 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.



36

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 1000 mg
Trial 1 (n=184) (n=273)
Mean change from baseline:

Modified total sharp score 2.30 1.01*

Erosion score 1.32 0.60*

Joint space narrowing score 0.98 0.41**

Proportion of patients with no radiographic change 46% 53%, NS
Proportion of patients with no erosive change 52% 60%, NS
150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX by one year
* p < 0.05, ** p < 0.001. Abbreviation: NS, non significant

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

Physical function and quality of life outcomes
Significant reductions in disability index (HAQ-DI) and fatigue (FACIT-Fatigue) scores were 
observed in patients treated with rituximab compared to patients treated with methotrexate alone. The 
proportions of rituximab treated patients showing a minimal clinically important difference (MCID) in 
HAQ-DI (defined as an individual total score decrease of > 0.22) was also higher than among patients 
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, a significantly higher proportion of patients achieved MCIDs for these scores (Table 14).

Table 14 Physical Function and Quality of Life outcomes at week 24 in Trial 1
Outcome† Placebo+MTX Rituximab+MTX

(2 x 1000 mg)
n=201 n=298

Mean change in HAQ-DI 0.1 -0.4***

% HAQ-DI MCID 20% 51%
Mean change in FACIT-T -0.5 -9.1***

n=197 n=294
Mean change in SF-36 PHS 0.9 5.8***

% SF-36 PHS MCID 13% 48%***

Mean change in SF-36 MHS 1.3 4.7**

% SF-36 MHS MCID 20% 38%*

† Outcome at 24 weeks
Significant difference from placebo at the primary time point: * p < 0.05, **p < 0.001 ***p ≤ 0.0001 
MCID HAQ-DI ≥ 0.22, MCID SF-36 PHS > 5.42, MCID SF-36 MHS > 6.33

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.



37

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.

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.



38

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

Clinical laboratory findings

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

Paediatric population

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 severe active granulomatosis with polyangiitis 
(75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator, 
randomised, double-blind, multicentre, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (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 1000 mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose 
glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 
80 mg/day). Prednisone tapering was to be completed by 6 months from the start of trial treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a 
Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off 
glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%. 
The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission at 6 
months (Table 16).

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing 
disease (Table 17).



39

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.

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 complete remission at 12 months, and 39% of 
patients achieved complete remission at 18 months. In patients treated with cyclophosphamide 
(followed by azathioprine for maintenance of complete remission), 39% of patients achieved complete 
remission at 12 months, and 33% of patients achieved complete remission 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 



40

per day) for at least 18 months after randomization. Prednisone dose tapering and the decision to stop 
prednisone treatment after month 18 were left at the investigator’s discretion.

All patients were followed until month 28 (10 or 6 months, respectively, after the last rituximab 
infusion or azathioprine dose). Pneumocystis jirovecii pneumonia prophylaxis was required for all 
patients with CD4+ T-lymphocyte counts less than 250 per cubic millimeter.

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

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

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

Figure 3: Cumulative incidence over time of first major relapse

Survival Time (Months)

Number of Subjects with Major Relapse
Azathioprine 0 0 3 3 5 5 8 8 9 9 9 10 13 15 17
Rituximab 0 0 0 0 1 1 1 1 1 1 1 1 3 3 3
Number of subjects at risk
Azathioprine 59 56 52 50 47 47 44 44 42 41 40 39 36 34 0
Rituximab 58 56 56 56 55 54 54 54 54 54 54 54 52 50 0

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

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 

Percent
age of

Patients
with
First

Major

Relapse



41

(74 pemphigus vulgaris [PV] and 16 pemphigus foliaceus [PF]) in this randomised, open-label, 
controlled, multicentre study. Patients were between 19 and 79 years of age and had not received prior 
therapies for pemphigus. In the PV population, 5 (13%) patients in the rituximab group and 3 (8%) 
patients in the standard prednisone group had moderate disease and 33 (87%) patients in the rituximab
group and 33 (92%) patients in the standard-dose prednisone group had severe disease according to 
disease severity defined by Harman’s criteria. 

Patients were stratified by baseline disease severity (moderate or severe) and randomised 1:1 to 
receive either rituximab and low-dose prednisone or standard-dose prednisone. Patients randomised to 
the rituximab group received an initial intravenous infusion of 1000 mg rituximab on Study Day 1 in 
combination with 0.5 mg/kg/day oral prednisone tapered off over 3 months if they had moderate 
disease or 1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease, and a 
second intravenous infusion of 1000 mg on Study Day 15. Maintenance infusions of rituximab 500 mg 
were administered at months 12 and 18. Patients randomised to the standard-dose prednisone group 
received an initial 1 mg/kg/day oral prednisone tapered off over 12 months if they had moderate 
disease or 1.5 mg/kg/day oral prednisone tapered off over 18 months if they had severe disease. 
Patients in the rituximab group who relapsed could receive an additional infusion of rituximab
1000 mg in combination with reintroduced or escalated prednisone dose. Maintenance and relapse 
infusions were administered no sooner than 16 weeks following the previous infusion. 

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

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-valuea 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 
b95% 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).



42

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

Post-hoc retrospective laboratory evaluation 
A total of 19/34 (56%) patients with PV, who were treated with rituximab, tested positive for ADA 
antibodies by 18 months. The clinical relevance of ADA formation in rituximab-treated PV patients is 
unclear.

5.2 Pharmacokinetic properties

Non-Hodgkin’s lymphoma

Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple 
infusions of rituximab as a single agent or in combination with CHOP therapy (applied rituximab
doses ranged from 100 to 500 mg/m2), the typical population estimates of nonspecific clearance (CL1), 
specific clearance (CL2) likely contributed by B cells or tumour burden, and central compartment 
volume of distribution (V1) were 0.14 L/day, 0.59 L/day, and 2.7 L, respectively. The estimated 
median terminal elimination half-life of rituximab was 22 days (range, 6.1 to 52 days). Baseline
CD19-positive cell counts and size of measurable tumour lesions contributed to some of the variability 
in CL2 of rituximab in data from 161 patients given 375 mg/m2 as an intravenous infusion for 4 weekly 
doses. Patients with higher CD19-positive cell counts or tumour lesions had a higher CL2. However, a 
large component of inter-individual variability remained for CL2 after correction for CD19-positive 
cell counts and tumour lesion size. V1 varied by body surface area (BSA) and CHOP therapy. This 
variability in V1 (27.1% and 19.0%) contributed by the range in BSA (1.53 to 2.32 m2) and concurrent 
CHOP therapy, respectively, were relatively small. Age, gender and WHO performance status had no 
effect on the pharmacokinetics of rituximab. This analysis suggests that dose adjustment of rituximab
with any of the tested covariates is not expected to result in a meaningful reduction in its 
pharmacokinetic variability.

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

Upon administration of rituximab at a dose of 375 mg/m2 as an intravenous infusion at weekly 
intervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusion, 
spanning from a mean of 243 µg/mL (range, 16 – 582 µg/mL) after the first infusion to 550 µg/mL 
(range, 171 – 1177 µg/mL) after the eighth infusion.

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



43

Chronic lymphocytic leukaemia

Rituximab was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to 
500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL 
patients. The mean Cmax (N=15) was 408 µg/mL (range, 97 – 764 µg/mL) after the fifth 500 mg/m2

infusion and the mean terminal half-life was 32 days (range, 14 – 62 days).

Rheumatoid arthritis

Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean 
terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day 
(range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 l (range, 1.7 to
7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic 
clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis 
revealed that BSA and gender were the most significant covariates to explain inter-individual 
variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume 
of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic 
differences are not considered to be clinically relevant and dose adjustment is not required. No 
pharmacokinetic data are available in patients with hepatic or renal impairment.

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

The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg 
upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was 
170 to 175 µg/mL for 2 x 500 mg dose and 317 to 370 µg/mL for 2 x 1000 mg dose. Cmax following 
second infusion, was 207 µg/mL for the 2 x 500 mg dose and ranged from 377 to 386 µg/mL for the 
2 x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second 
course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose. PK 
parameters for rituximab were comparable over the two treatment courses.

The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following the 
same dosage regimen (2 x 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serum 
concentration of 369 µg/mL and a mean terminal half-life of 19.2 days.

Granulomatosis with polyangiitis and microscopic polyangiitis

Based on the population pharmacokinetic analysis of data in 97 patients with granulomatosis with 
polyangiitis and microscopic polyangiitis who received 375 mg/m2 rituximab once weekly for four 
doses, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days).
Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726 L/day) 
and 4.50 L (range 2.25 to 7.39 L) respectively. The PK parameters of rituximab in these patients 
appear similar to what has been observed in rheumatoid arthritis patients.

5.3 Preclinical safety data

Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in 
cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of B 
cells in peripheral blood and in lymphoid tissue.



44

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

L-histidine 
L-histidine hydrochloride monohydrate 
Disodium edetate
Polysorbate 80
Sucrose
Water for injection

6.2 Incompatibilities

No incompatibilities between Ruxience and polyvinyl chloride or polyethylene bags or infusion sets 
have been observed.

6.3 Shelf life

Unopened vial

24 months

Diluted medicinal product

 After aseptic dilution in sodium chloride solution
The prepared infusion solution of Ruxience in 0.9% sodium chloride solution is physically and 
chemically stable for 35 days at 2 °C – 8 °C plus an additional 24 hours at ≤ 30 °C. 

 After aseptic dilution in D-glucose solution 
The prepared infusion solution of Ruxience in 5% D-glucose solution is physically and chemically 
stable for 24 hours at 2 °C – 8 °C plus an additional 24 hours at ≤ 30 °C.

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

6.4 Special precautions for storage

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



45

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

6.5 Nature and contents of container

Ruxience 100 mg concentrate for solution for infusion

Clear Type I glass vials with chlorobutyl rubber stopper containing 100 mg of rituximab in 10 mL. 
Pack of 1 vial.

Ruxience 500 mg concentrate for solution for infusion

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

6.6 Special precautions for disposal and other handling

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

Aseptically withdraw the necessary amount of Ruxience 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

Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

Ruxience 100 mg concentrate for solution for infusion

EU/1/20/1431/001

Ruxience 500 mg concentrate for solution for infusion

EU/1/20/1431/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 01 April 2020



46

10. DATE OF REVISION OF THE TEXT

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



47

ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURER 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



48

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

Name and address of the manufacturer of the biological active substance(s)

Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Straße 65
88397 Biberach an der Riss
Germany

Name and address of the manufacturer responsible for batch release

Pfizer Manufacturing Belgium NV
Rijksweg 12
2870 Puurs
Belgium

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 (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the pharmacovigilance activities and 
interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and 
any agreed and subsequent updates of the RMP.

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

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

 Additional risk minimisation measures

Non-oncology indications:

The MAH must ensure that all physicians who are expected to prescribe Ruxience are provided with
the following:



49

Product information
Physician information
Patient information
Patient Alert card

The Physician information about Ruxience should contain the following key elements:
 The need for close supervision during administration in an environment where full

resuscitation facilities are immediately available
 The need to check, prior to Ruxience treatment, for infections, for immunosuppression, for

prior/current medication affecting the immune system and recent history of, or planned,
vaccination

 The need to monitor patients for infections, especially PML, during and after Ruxience
treatment

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

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

 The need to provide patients with the Patient Alert Card with each infusion

The Patient information about Ruxience should contain the following key elements:
 Detailed information on the risk of infections and PML
 Information on the signs and symptoms of infections, especially PML, and the need to

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

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

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

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

Oncology indications:

The MAH must ensure that all physicians who are expected to prescribe Ruxience are provided with 
the following: 
Product information
Physician information 

The Physician information about Ruxience should contain the following key elements: 
 Information that the product should be administered as IV only to avoid administration 

route errors.

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



50

ANNEX III

LABELLING AND PACKAGE LEAFLET



51

A. LABELLING



52

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Ruxience 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

L-histidine, L-histidine hydrochloride monohydrate, disodium edetate, polysorbate 80, sucrose, water 
for injection.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion 
100 mg / 10 mL
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For intravenous use after dilution 
Read the package leaflet before use.

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

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



53

9. SPECIAL STORAGE CONDITIONS

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

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/20/1431/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER -- HUMAN READABLE DATA

PC:
SN:
NN:



54

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING 
UNITS

VIAL LABEL

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

Ruxience 100 mg sterile concentrate 

rituximab

2. METHOD OF ADMINISTRATION

I.V. after dilution

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

100 mg / 10 mL

6. OTHER



55

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Ruxience 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

L-histidine, L-histidine hydrochloride monohydrate, disodium edetate, polysorbate 80, sucrose, water 
for injection.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion 
500 mg / 50 mL
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For intravenous use after dilution 
Read the package leaflet before use.

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

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



56

9. SPECIAL STORAGE CONDITIONS

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

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/20/1431/002

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:



57

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL

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

Ruxience 500 mg sterile concentrate

rituximab

2. METHOD OF ADMINISTRATION

For intravenous use after dilution

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

500 mg / 50 mL

6. OTHER



58

PATIENT ALERT CARD TEXT FOR NON-ONCOLOGY INDICATIONS

Ruxience 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 
Ruxience

 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 Ruxience.

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

When should I not have Ruxience?

Do not have Ruxience 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 cough all the time

 Weight loss

 Pain without injuring yourself

 Feeling generally unwell or listless.

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

You should also tell them about your 
Ruxience treatment.

What else do I need to know?

Rarely Ruxience 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 Ruxience treatment.

Where can I get more information?

See the Ruxience 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.



59

B. PACKAGE LEAFLET



60

Package leaflet: Information for the patient
Ruxience 100 mg concentrate for solution for infusion
Ruxience 500 mg concentrate for solution for infusion

rituximab

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

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

side effects not listed in this leaflet. See section 4.

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

1. What Ruxience is and what it is used for 

What Ruxience is
Ruxience 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 Ruxience is used for
Ruxience may be used for the treatment of several different conditions in adults. Your doctor may 
prescribe Ruxience 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.
Ruxience can be given alone or with other medicines called “chemotherapy”.
In patients where the treatment is working, Ruxience 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. Ruxience in combination with chemotherapy destroys these cells which are gradually 
removed from the body by biological processes.

c) Rheumatoid arthritis
Ruxience 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. Ruxience is used 
to treat rheumatoid arthritis in people who have already tried some other medicines which have either 



61

stopped working, have not worked well enough or have caused side effects. Ruxience is usually taken 
together with another medicine called methotrexate.

Ruxience slows down the damage to your joints caused by rheumatoid arthritis and improves your 
ability to do normal daily activities.

The best responses to Ruxience 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
Ruxience 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 
Ruxience is used for the treatment of patients with moderate to severe pemphigus vulgaris. Pemphigus 
vulgaris is an autoimmune condition that causes painful blisters on the skin and lining of the mouth, 
nose, throat and genitals.

2. What you need to know before you use Ruxience

Do not take Ruxience
 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)
 if you have a severe active infection at the moment
 if you have a weak immune system.
 if 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 Ruxience if any of the above apply to you. If you are not sure, talk to your doctor, 
pharmacist or nurse before you are given Ruxience.

Warnings and precautions
It is important that you and your doctor record the brand name and batch number of your medication.

Talk to your doctor, pharmacist or nurse before you are given Ruxience if:

 you have ever had or might now have a hepatitis infection. This is because in a few cases, 
Ruxience 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 Ruxience. Your doctor may need to take special care of you during your treatment with 
Ruxience.

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 Ruxience help to fight infection and you should wait until the infection has passed before you 



62

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

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

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

 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 Ruxience.

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 Ruxience 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 Ruxience. You must also do this for 12 months after your last treatment with Ruxience.
Do not breast-feed while you are being treated with Ruxience. Also do not breast-feed for 12 months 
after your last treatment with Ruxience. This is because Ruxience may pass into breast milk.

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

Ruxience sodium content
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’.

3. How Ruxience is given 

How it is given
Ruxience 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 Ruxience as a drip (intra-venous infusion).

Medicines given before each Ruxience administration
Before you are given Ruxience, you will be given other medicines (pre-medication) to prevent or 
reduce possible side effects.



63

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 Ruxience alone

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

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

 If you respond well to treatment, you may be given Ruxience 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 Ruxience in combination with chemotherapy, you will receive Ruxience
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 Ruxience 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 Ruxience are possible. Depending on the signs and symptoms of 
your disease, your doctor will decide when you should receive more Ruxience. This may be months 
from now.

d) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis
Treatment with Ruxience uses four separate infusions given at weekly intervals. Corticosteroids will 
usually be given by injection before the start of Ruxience 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 Ruxience 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 Ruxience (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 Ruxience 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 



64

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 
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 
Ruxience 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 Ruxience.
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



65

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

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

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

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

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

reaching the body organs
 swelling of the stomach.

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

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

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

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

 kidney failure 
 severe vision loss

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

cases
 hearing loss, loss of other senses

b) If you are being treated for 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.



66

Common side effects (may affect up to 1 in 10 people):
 infections such as bronchial tube inflammation (bronchitis)
 a feeling of fullness or a throbbing pain behind the nose, cheeks and eyes (sinusitis), pain in the 

abdomen, vomiting and diarrhoea, breathing problems
 fungal foot infection (athlete’s foot)
 high cholesterol levels in the blood
 abnormal sensations of the skin, such as numbness, tingling, pricking or burning, sciatica, 

migraine, dizziness
 loss of hair
 anxiety, depression
 indigestion, diarrhoea, acid reflux, irritation and /or ulceration of the throat and the mouth
 pain in the tummy, back, muscles and/or joints

Uncommon side effects (may affect up to 1 in 100 people):
 excess fluid retention in the face and body
 inflammation, irritation and / or tightness of the lungs, and throat, coughing
 skin reactions including hives, itching and rash
 allergic reactions including wheezing or shortness of breath, swelling of the face and tongue, 

collapse

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



67

 blocked or runny nose
 tight or painful muscles
 pain in the muscles or in the hands or feet
 low number of red blood cells (anaemia)
 low numbers of platelets in the blood
 an increase in the amount of potassium in the blood
 changes in the rhythm of the heart, or the heart beating faster than normal

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

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

 recurrence of a previous Hepatitis B infection

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

Ruxience may also cause changes in laboratory tests carried out by your doctor.
If you are having Ruxience with other medicines, some of the side effects you may get may be due to 
the other medicines.

Reporting of side effects
If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Ruxience

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.



68

6. Contents of the pack and other information

What Ruxience contains

 The active ingredient in Ruxience 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 L-histidine, L-histidine hydrochloride monohydrate, disodium 
edetate, polysorbate 80, sucrose, water for injection.

What Ruxience looks like and contents of the pack

Ruxience is a clear to slightly opalescent, colourless to pale brownish-yellow solution, supplied as a 
concentrate for solution for infusion [sterile concentrate]. 
10 mL vial – Pack of 1 vial
50 mL vial – Pack of 1 vial

Marketing Authorisation Holder

Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium

Manufacturer

Pfizer Manufacturing Belgium NV
Rijksweg 12
2870 Puurs
Belgium

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

België/Belgique/Belgien
Luxembourg/Luxemburg
Pfizer NV/SA
Tél/Tel: +32 (0)2 554 62 11

Kύπρος
PFIZER EΛΛAΣ A.E. (CYPRUS BRANCH)
T: +357 22 817690

Česká Republika
Pfizer, spol. s r.o.
Tel: +420-283-004-111

Magyarország
Pfizer Kft.
Tel: +36 1 488 3700

Danmark
Pfizer ApS
Tlf: +45 44 201 100

Malta
Vivian Corporation Ltd.
Tel: +356 21344610

Deutchland
Pfizer Pharma PFE GmbH
Tel: +49 (0)800 8535555

Nederland
Pfizer bv
Tel: +31 (0)10 406 43 01



69

България
Пфайзер Люксембург САРЛ,
Клон България
Teл: +359 2 970 4333

Norge
Pfizer AS
Tlf: +47 67 52 61 00

Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 666 7500

Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0

Ελλάδα
PFIZER EΛΛAΣ A.E.
Τηλ.: +30 210 67 85 800

Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00

España
Pfizer S.L.
Tel: +34 91 490 99 00

Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500

France
Pfizer 
Tél: +33 (0)1 58 07 34 40

România
Pfizer România S.R.L
Tel: +40 (0) 21 207 28 00

Hrvatska
Pfizer Croatia d.o.o.
Tel: +385 1 3908 777

Slovenija
Pfizer Luxembourg SARL, Pfizer, podružnica
za svetovanje s področja farmacevtske
dejavnosti, Ljubljana
Tel: +386 (0)1 52 11 400

Ireland
Pfizer Healthcare Ireland
Tel: +1800 633 363 (toll free)
Tel: +44 (0)1304 616161

Slovenská Republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421 2 3355 5500

Ísland
Icepharma hf.
Tel: +354 540 8000

Suomi/Finland
Pfizer PFE Finland Oy
Puh/Tel: +358 (0)9 430 040

Italia
Pfizer S.r.l. 
Tel: +39 06 33 18 21

Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel. +371 67035775

United Kingdom
Pfizer Limited
Tel: +44 (0)1304 616161

Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000

This leaflet was last revised in <{MM/YYYY}><{month YYYY}>.



70

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 OF THE BIOLOGICAL ACTIVE SUBSTANCE ANDMANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET