Non-Hodgkin’s lymphoma
Monotherapy in patients with CD20-positive follicular non-Hodgkin’s lymphoma (stage
III–IV) who have relapsed after, or failed to respond to, chemotherapy.

Treatment of previously untreated patients with CD20-positive follicular non-Hodgkin’s
lymphoma (stage III–IV) with high tumour burden in combination with CVP or CHOP.
Responders may be administered maintenance therapy with rituximab monotherapy for 2
years.

Maintenance therapy of patients with relapsed or refractory CD20-positive follicular non-
Hodgkin’s lymphoma (stage III–IV) who have responded to induction therapy with CHOP

with or without rituximab.
Treatment of patients with CD20-positive diffuse large B-cell non-Hodgkin’s lymphoma
(DLBCL) in combination with standard CHOP (8 cycles of cyclophosphamide,
doxorubicin, vincristine and prednisone).
Use in combination with fludarabine and cyclophosphamide (R-FC) for patients requiring
treatment for chronic lymphocytic leukemia (CLL). Patients previously treated with
fludarabine should have responded for a period of at least 6 months.

Rheumatoid arthritis
MabThera in combination with methotrexate (MTX) is indicated for the treatment of adult
patients with moderately severe to severe active rheumatoid arthritis after failure of one or
more tumour necrosis factor (TNF) inhibitor therapies.
ANCA-associated vasculitis (AAV)
MabThera is indicated in combination with corticosteroids for the treatment of patients
with severe active ANCA-associated vasculitis (granulomatosis with polyangiitis [also
known as Wegener’s granulomatosis] and microscopic polyangiitis).

MabThera infusions should be administered in a medical environment in which the
resources for effective resuscitation can be immediately deployed. The infusions should be
administered under the direct supervision of a physician experienced in the respective
specialty. MabThera can be administered on an ambulant basis. Patients who develop
respiratory symptoms or hypotension should be monitored for at least 24 hours.
First infusion: The recommended initial infusion rate is 50 mg/h; after the first 60 minutes
the rate can be escalated in 50 mg/h increments every 30 minutes to a maximum of
400 mg/h.

Subsequent infusions: Subsequent infusions of MabThera can be started at a rate of
100 mg/h and increased by 100 mg/h increments every 30 minutes to a maximum of
400 mg/h.
Patients should be closely monitored for the onset of cytokine release syndrome (see
Warnings and precautions). In patients who develop evidence of severe adverse drug
reactions (ADRs), especially severe dyspnea, bronchospasm or hypoxia, the infusion
should be interrupted immediately. Patients with follicular non-Hodgkin’s lymphoma,
DLBCL or CLL should also be evaluated for evidence of tumour lysis syndrome. Patients
with pre-existing respiratory failure or pulmonary tumour infiltration must undergo a chest
X-ray. In all patients the infusion should not be restarted until all clinical signs and
symptoms have fully resolved and laboratory values have returned to normal, at which
point the infusion can be resumed at up to half the previous rate. If the same severe adverse
drug reactions recur, consideration should be given to stopping the treatment.

Non-Hodgkin’s lymphoma (NHL)
Glucocorticoid premedication is not generally required because MabThera is combined in
this context with glucocorticoid-containing chemotherapy such as CHOP or CVP.
Reducing the dose of MabThera is not recommended (except in CLL).
Follicular non-Hodgkin’s lymphoma

Premedication consisting of an analgesic/antipyretic (e.g. paracetamol) and an anti-
histaminic drug (e.g. diphenhydramine) should always be administered before each

infusion of MabThera/Rituxan (30 to 60 minutes before the start of the infusion).
Premedication with glucocorticoids should also be considered, particularly if
MabThera/Rituxan is not given in combination with steroid-containing chemotherapy.
Monotherapy: The recommended dosage is 375 mg/m2

body surface area weekly for

4 weeks as an intravenous infusion.
Combination therapy: The recommended dosage of MabThera in combination with CVP
or CHOP chemotherapy is 375 mg/m2

body surface area once per cycle for 8 treatment
cycles. The dose of MabThera is given on day 1 of each chemotherapy cycle after oral
administration of the glucocorticoid component of the chemotherapy.
Maintenance therapy
In untreated patients MabThera is administered every 2 months (375 mg/m2

body surface

area).
In the treatment of recurrence MabThera is administered every 3 months (375 mg/m2
body

surface area).
The maintenance dose should be given until disease progression or for a maximum
duration of two years.

Diffuse large B-cell non-Hodgkin’s lymphoma

Premedication consisting of an analgesic/antipyretic (e.g. paracetamol) and an anti-
histaminic drug (e.g. diphenhydramine) should always be administered before each

infusion of MabThera/Rituxan (30 to 60 minutes before the start of the infusion).
Premedication with glucocorticoids should also be considered, particularly if
MabThera/Rituxan is not given in combination with steroid-containing chemotherapy.
MabThera should be used in combination with CHOP chemotherapy. The recommended
dosage of MabThera is 375 mg/m2

body surface area once every 3 weeks for 8 treatment
cycles. The dose of MabThera is administered on day 1 of each chemotherapy cycle after
i.v. administration of the glucocorticoid component of the CHOP chemotherapy.
Chronic lymphocytic leukemia (CLL)
It is recommended that 48 hours before the start of treatment prophylaxis with adequate
fluid intake and administration of urostatic agents be initiated in order to reduce the risk of
tumour lysis syndrome.
In addition, consideration should be given to premedication with glucocorticoids shortly
before the start of the infusion with MabThera in order to reduce the frequency and
severity of acute infusion reactions and/or of cytokine release syndrome.
The recommended dose of MabThera in previously untreated or relapsed/refractory
patients is 375 mg/m2

body surface area on day 1 of the first treatment cycle, followed by

500 mg/m2

body surface area on day 1 of cycles 2–6 (at four-week intervals). Fludarabine

25 mg/m2

and cyclophosphamide 250 mg/m2

are given on days 2, 3 and 4 in the first cycle

and days 1–3 in cycles 2–6.
The following dosage adjustments are recommended if severe infections occur or if grade
3 or 4 cytopenia (anemia, neutropenia, thrombocytopenia) that is not indicative of bone
marrow involvement occurs on day 28 of a cycle:

Treatment can be postponed for 2 weeks and the dose of fludarabine and cyclo-
phosphamide can be reduced by 25% in the following cycles.

In the event that after this dose reduction a second episode of grade 3–4 cytopenia occurs
on day 28 of a cycle independently of bone marrow involvement, treatment can once again
be postponed by up to 2 weeks and the dose of fludarabine and cyclophosphamide can be
reduced by a further 25%. This results in a dose equivalent to 50% of the normal
fludarabine/cyclophosphamide dose.

Rheumatoid arthritis

Premedication consisting of an analgesic/antipyretic (e.g. paracetamol) and an anti-
histaminic drug (e.g. diphenhydramine) should always be administered before each

infusion of MabThera/Rituxan (30 to 60 minutes before the start of the infusion).
Premedication with glucocorticoids should also be administered in order to reduce the
frequency and severity of infusion-related reactions. Patients should receive 100 mg i.v.
methylprednisolone to be completed 30 minutes prior to each MabThera/Rituxan infusion.

A treatment cycle with MabThera consists of two i.v. infusions of 1,000 mg given at an
interval of 2 weeks. Depending on the course of the disease, additional treatment cycles
can be given.
After the infusion has been completed, the intravenous line should be left in place for at
least one hour so that if necessary drugs can be administered intravenously. If no
undesirable effects occur during this period, the intravenous line can then be removed.
In a dose-finding study in a less treatment-resistant patient population that had failed to
respond to treatment with DMARDs (disease-modifying antirheumatic drugs), treatment
with 2 × 500 mg per cycle proved similarly effective as 2 × 1,000 mg (in terms of the
endpoint ACR 20). Doses of less than 2 × 500 mg per cycle were not investigated.
The requirement for further cycles should be assessed 24 weeks after the previous cycle on
the basis of residual or recurrent disease activity. Retreatment should be given if residual
disease activity exceeds a DAS28-ESR score of 2.6. If the DAS28-ESR score is less than
2.6, retreatment should be given as soon as disease activity increases again (to DAS28-
ESR >2.6).
Treatment with MabThera should only be continued in patients whose DAS28-ESR score
has decreased by at least 1.2 units after two treatment cycles.
In patients previously treated with TNF inhibitors, treatment with etanercept must have
been discontinued for at least 4 weeks, and with infliximab or adalimumab for at least 8
weeks, before starting MabThera treatment.
The use of MabThera is not recommended in MTX-naive patients since a favourable
benefit-risk ratio has not been demonstrated.

ANCA-associated vasculitis
Treatment should only be conducted by physicians experienced in the treatment of
rheumatic and immunological diseases.
Before each MabThera infusion (30 to 60 minutes before starting the infusion)
premedication must always be administered with an analgesic/antipyretic (e.g.
paracetamol) and an antihistamine (e.g. diphenhydramine).
The recommended dosage of MabThera for the treatment of ANCA-associated vasculitis is
375 mg/m2

body surface area administered once weekly as an intravenous infusion for

4 weeks.
For the treatment of severe vasculitis symptoms it is recommended that MabThera be
combined with intravenous methylprednisolone 1,000 mg daily for 1 to 3 days, followed
by oral prednisone 1 mg/kg body weight/day (not to exceed 80 mg/day and to be tapered as
rapidly as possible according to clinical need) during and after treatment with MabThera.

First infusion: The recommended initial infusion rate of MabThera is 50 mg/h; it may
subsequently be increased in 50 mg/h increments every 30 minutes to a maximum of
400 mg/h.
Subsequent infusions: Subsequent MabThera infusions may be started at an infusion rate of
100 mg/h and increased in 100 mg/h increments every 30 minutes to a maximum of
400 mg/h.
The safety and efficacy of treatment with subsequent cycles of MabThera have not been
determined.
In patients with ANCA-associated vasculitis Pneumocystis jiroveci pneumonia (PCP)
prophylaxis is recommended as needed during and after MabThera treatment.

Special dosage instructions
Use in children and adolescents
The use and safety of MabThera in children and adolescents have not been investigated.
Elderly patients
No dosage adjustment is required in elderly patients (>65 years).
Patients with hepatic or renal impairment
No experience is available in patients with hepatic or renal impairment.

In order to improve traceability of biological medicinal products, the tradename MabThera
should be clearly recorded (or stated) in the patient file. Replacement by another biological
medicinal product requires the prescriber’s consent. The data in this prescribing
information apply only to MabThera.
Progressive multifocal leukoencephalopathy
Cases of progressive multifocal leukoencephalopathy (PML) have been reported during or
after the use of MabThera. Two cases of fatal PML in NHL patients were also observed in
a clinical phase III study after disease progression and retreatment. The majority of patients
had received MabThera in combination with chemotherapy or in a context of

hematopoietic stem cell transplantation. In the differential diagnosis of patients developing
neurological symptoms the possibility of PML must be considered.
Patients should be monitored at regular intervals for emergent or worsening symptoms
indicative of PML. PML is frequently fatal and resistant to all therapy. PML signs and
symptoms are varied, progress over days to weeks and may comprise increasing weakness
in one side of the body or clumsiness in the limbs, loss of balance, visual disturbances and
impairment of cognition, memory and orientation, leading to confusion and personality
changes.
If in doubt, further investigations should be considered, including MRI (preferably
contrast-enhanced), testing of the cerebrospinal fluid for JC virus DNA and serial
neurological assessment. The physician should be alert to signs and symptoms indicative
of PML, in particular those unnoticed by the patient (e.g. cognitive, neurological or
psychiatric signs). The patient should in addition be advised to inform their partner or
carers about their treatment since these may observe signs that escape the patient’s notice.
If PML is suspected, prompt neurological workup is indicated and treatment should be
suspended until PML is excluded. If PML is confirmed, MabThera must be permanently
withdrawn.
Following reconstitution of the immune system, stabilisation or improvement has been
observed in immunosuppressed patients with PML. It is not known whether early detection
of PML and suspension of MabThera treatment could lead to similar stabilisation or
improvement.

Patients with hematological malignancies
Tumour lysis syndrome: MabThera brings about rapid lysis of benign and malignant
CD20-positive cells and can precipitate tumour lysis syndrome with hyperuricemia,
hyperkalemia, hypocalcemia, hyperphosphatemia, elevated LDH levels and acute renal
failure. Patients with a high number (>25,000/mm3

) of circulating malignant cells or a high
tumour burden (lesions >10 cm) are at higher risk of tumour lysis syndrome and should be
treated with extreme caution. In patients at risk for the development of tumour lysis
syndrome the need for appropriate prophylaxis should be considered. In these patients the
infusion rate should be reduced or infusion spread over 2 days in the first cycle, and in all
subsequent cycles if the lymphocyte count remains above 25,000/mm3

. The patients should

be monitored particularly closely during administration of the first infusion.
Infusion-related reactions

Treatment with MabThera leads to release of cytokines and is associated with infusion-
related reactions, especially after administration of the first dose. The incidence of

infusion-related reactions decreased from 77% (7% grade 3/4) with the first infusion to
approximately 30% (2% grade 3/4) with the fourth infusion and to 14% (no grade 3/4

events) with the eighth infusion. Severe infusion-related reactions may be clinically
indistinguishable from hypersensitivity reactions or cytokine release syndrome. Severe
infusion-related reactions with fatal outcome have been reported. Severe infusion-related
reactions, which are characterised by pulmonary events, generally commence within
30 minutes to two hours after the start of the first MabThera infusion and in some cases
have also included rapid tumour lysis and signs of tumour lysis syndrome as well as fever,
chills, rigors, hypotension, urticaria, angioedema and other signs and symptoms (see
Undesirable effects).
It is recommended that infusion-related reactions be treated with diphenhydramine and
acetaminophen. Additional treatment with bronchodilators or intravenous saline solution
may be indicated. In most cases the infusion can be continued with a 50% reduction of
infusion rate (e.g. from 100 mg/h to 50 mg/h) after complete resolution of signs and
symptoms. Most patients other than those with life-threatening infusion-related reactions
were able to complete the treatment cycle with MabThera. Only rarely have severe
infusion-related reactions recurred during subsequent treatment of patients whose signs and
symptoms have resolved completely.
The occurrence of anaphylactic and other hypersensitivity reactions has been reported after
intravenous administration of proteins to patients. Adrenaline, antihistamines and
glucocorticoids should be available for immediate use in the event of a hypersensitivity
reaction during administration of MabThera.
Pulmonary events
Pulmonary events including hypoxia, pulmonary infiltrates and acute respiratory failure
have occurred. Many of these events were preceded by severe bronchospasm and dyspnea.
In some cases the signs and symptoms worsened, while in other cases an initial
improvement was followed by a clinical deterioration. Patients with pulmonary events or
other severe infusion reactions must therefore be closely monitored until their signs and
symptoms have resolved completely. Patients with a history of respiratory failure or with
pulmonary tumour infiltration are at greater risk of an unfavourable outcome and should
therefore be treated with greater caution. Acute respiratory failure can be accompanied by
events such as pulmonary interstitial infiltration visible on a chest radiograph and edema.
The syndrome generally appears within one to two hours after the start of the first infusion.
In patients with severe pulmonary events the infusion must be stopped immediately and
symptomatic therapy initiated.
Cardiovascular
Since transient hypotension may occur during MabThera infusion, consideration should be
given to withholding antihypertensive medications 12 hours prior to and throughout

MabThera infusion. When MabThera was administered, cases were observed in which pre-
existing ischemic heart disease became manifest and caused symptoms such as angina

pectoris, myocardial infarction, atrial fibrillation and atrial flutter. Patients with a history of
heart disease (e.g. angina pectoris, cardiac arrhythmias such as atrial flutter or fibrillation,

heart failure or myocardial infarction) should be closely monitored during the infusion.
Patients with severe heart failure (NYHA class IV) should not be treated.
Monitoring of blood counts
Caution should be exercised when treating patients with neutrophil counts of <1.5 × 109
/l

and/or platelet counts of <75 × 109

/l, as clinical experience with such patients is limited.
As with other tumour therapies, regular monitoring of full blood count, including platelet
count, is indicated.
Immunisation
The safety of immunisation with vaccines, especially live vaccines, following MabThera
therapy has not been studied, nor whether a primary humoral response to vaccines is
possible.
Patients treated with MabThera must not receive live vaccines. If necessary, they may be
immunised with non-live vaccines, although a reduced response rate must be expected. In a
non-randomised study, patients receiving MabThera monotherapy had a lower response
rate (when assessed for a >2-fold increase in antibody titre) to testing with tetanus recall
antigen (16% vs 81%) and keyhole limpet hemocyanin (KLH; 4% vs 76%), compared to
untreated controls.
Mean pretherapeutic antibody titres against a panel of antigens (Streptococcus
pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months
after treatment with MabThera.
Skin reactions
Severe mucocutaneous reactions, some with fatal outcome, have been reported in isolated
patients treated with MabThera. These reactions occurred between 1 and 13 weeks after the
start of treatment. Affected patients should receive no further infusions and must undergo a
medical examination immediately. A skin biopsy is useful for distinguishing between
different skin reactions and determining subsequent treatment. The mucocutaneous
reactions reported included paraneoplastic pemphigus, lichenoid dermatitis and
vesiculobullous dermatitis. Nothing is known regarding the safety of retreatment with
MabThera in these cases.
Serious skin reactions, such as toxic epidermal necrolysis and Stevens-Johnson syndrome,
some of which were fatal, have been reported (see Undesirable effects). In such an event
treatment should be discontinued and only reintroduced after careful consideration of the
patient’s individual benefit-risk profile.
Serious viral infections
Patients with serious viral infections should not be treated with MabThera. Serious viral
infections, both new and reactivated or exacerbated, have been reported on treatment with
rituximab and have been fatal in isolated cases. The majority of patients had received
rituximab in combination with chemotherapy or in the context of hematopoietic stem cell
transplantation. Examples of such serious viral infections include infections with

herpesviruses (cytomegalovirus, varicella zoster virus, herpes simplex virus), JC virus
(progressive multifocal leukoencephalopathy [PML]) and hepatitis B or hepatitis C virus.
Cases of hepatitis B reactivation – including fulminant hepatitis, sometimes with fatal
outcome – have been reported; the majority of affected patients were also receiving
cytotoxic chemotherapy. Causality cannot be clearly distinguished.
Hepatitis B virus (HBV) screening according to local guidelines should be performed in all
patients before initiation of treatment with MabThera. Patients with active hepatitis B disease
should not be treated with MabThera. Patients with positive hepatitis B serology should consult a
liver disease specialist before the start of treatment and should be monitored and managed
according to usual local standard medical practice to prevent hepatitis B reactivation..
Gastrointestinal tract
Gastrointestinal perforation or obstruction, in a few cases leading to death, has been
observed in patients who received rituximab in combination with chemotherapy for the
treatment of non-Hodgkin’s lymphoma. Complaints of abdominal pain, especially at the
start of treatment, should prompt a thorough diagnostic evaluation and appropriate
treatment.
Nervous system disorders
There have been post-marketing reports of cases of posterior reversible encephalopathy
syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS). Signs and
symptoms included visual disturbances, headaches, seizures and altered mental state with
or without associated hypertension. The diagnosis of PRES/RPLS must be confirmed by
brain imaging. In the reported cases there were recognised risk factors for PRES/RPLS
including patients’ underlying disease, hypertension, immunosuppressive therapy and/or
chemotherapy.
Patients with rheumatoid arthritis and ANCA-associated vasculitis
The efficacy and safety of MabThera for the treatment of autoimmune diseases other than
rheumatoid arthritis and ANCA-associated vasculitis have not been studied.
An electrocardiogram should be performed before starting treatment of ANCA-associated
vasculitis.
Infusion-related reactions
Administration of MabThera can be associated with infusion reactions related to release of
cytokines and/or other chemical mediators. Signs and symptoms that indicate an infusion
reaction are headache, itch, fever, urticaria/rash, chills, pyrexia, sneezing, angioneurotic
edema, throat irritation, cough and bronchospasm – with or without associated hypotension
or hypertension. Premedication consisting of an analgesic/antipyretic drug and an
antihistaminic drug should always be administered before each infusion of
MabThera/Rituxan. For RA patients, premedication with glucocorticoids should also be
administered before each infusion of MabThera/Rituxan, in order to reduce the frequency 

and severity of infusion-related reactions (see Dosage and administration). Higher doses of
intravenous glucocorticoids were administered in ANCA-associated vasculitis patients.
For RA patients, most infusion-related events reported in clinical trials were mild to
moderate in severity. In clinical studies a severe infusion reaction occurred, independently
of dose, in 14 of 3,095 patients (<1%) with rheumatoid arthritis who received a first
infusion of MabThera. Severe infusion-related reactions with fatal outcome have been
reported in the post-marketing setting (in total approx. 150,000 treated RA patients).
Patients with pre-existing cardiac conditions and those who experienced prior
cardiopulmonary adverse reactions should be closely monitored.
In general, the proportion of patients experiencing an infusion reaction was higher after the
first infusion of a cycle than after the second infusion. Subsequent MabThera cycles were
better tolerated by patients than the first cycle.
The reported reactions were generally reversible when the infusion of MabThera was
administered more slowly or interrupted and an antipyretic, an antihistamine and – in
isolated cases and if required – oxygen, i.v. saline solution or bronchodilators and
glucocorticoids were administered. Depending on the severity of the infusion-related
reaction and the required interventions, temporarily or permanently discontinue
MabThera/Rituxan. In most cases the infusion can be continued with a 50% reduction of
infusion rate (e.g. from 100 mg/h to 50 mg/h) after complete resolution of signs and
symptoms.
Anaphylactic and other hypersensitivity reactions have been reported at the start of, during
and after i.v. administration of proteins to patients. Drugs for the treatment of
hypersensitivity reactions, e.g. adrenaline, antihistamines and glucocorticoids, should be
available for immediate use in the event that an allergic reaction occurs during
administration of MabThera.
Infusion reactions in ANCA-associated vasculitis patients were comparable to those
observed in RA patients.
No data are available on the safety of MabThera in patients with moderately severe heart
failure (NYHA class III). Cases of angina pectoris, cardiac arrhythmias such as atrial
flutter and fibrillation, heart failure or myocardial infarction have been observed on
treatment with MabThera. Therefore, in patients with a history of heart disease the risk for
cardiovascular complications due to infusion-related reactions should be considered before
treatment with MabThera is initiated, and such patients should be closely monitored during
administration of MabThera. Patients with severe heart failure (NYHA class IV) should
not be treated.
Since hypotension can occur during infusion of MabThera, consideration should be given
to withholding blood-pressure-lowering medications in the 12 hours preceding infusion of
MabThera.
Infections

The risk of infection is potentially increased after treatment with MabThera (see Contra-
indications). MabThera should not be administered to patients with active infection or severely impaired immune response (e.g. hypogammaglobulinemia, severely reduced CD4
or CD8 cell counts). Caution is required when MabThera is prescribed for patients with a
history of recurrent or chronic infection or an underlying disease that favours the
occurrence of severe infections (see Undesirable effects). Patients who develop an
infection after treatment with MabThera should be promptly investigated and appropriately
treated.
Hepatitis B infections
Cases of reactivation of hepatitis B infection, including some with fatal outcome, have
been reported in RA and AAV patients receiving MabThera.
Hepatitis B virus (HBV) screening according to local guidelines should be performed in all
patients before initiation of treatment with MabThera. Patients with active hepatitis B
disease should not be treated with MabThera. Patients with positive hepatitis B serology should
consult a liver disease specialist before the start of treatment and should be monitored and
managed according to usual local standard medical practice to prevent hepatitis B
reactivation.
Skin reactions
Serious skin reactions, such as toxic epidermal necrolysis and Stevens-Johnson syndrome,
some of which were fatal, have been reported (see Undesirable effects). In such an event
treatment should be discontinued and only reintroduced after careful consideration of the
patient’s individual benefit-risk profile.
Immunisation
In RA patients the physician should review vaccination status and follow local/national
immunisation guidelines for adults against infectious diseases prior to treatment with
MabThera. Vaccination should be completed at least 4 weeks prior to first administration
of MabThera.
Vaccination with live viral vaccines should not be performed during treatment with
MabThera.
Response to inactivated vaccines may be reduced during and after treatment with
MabThera. Comparison of patients treated with either MabThera and methotrexate or
methotrexate alone showed similar response rates to tetanus recall antigen (39% vs 42%)
and decreased response rates to pneumococcal polysaccharide vaccine (43% vs 82%)
6 months after completing MabThera treatment.
In repeat treatment over one year the proportion of patients with positive antibody titres
against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were
generally similar to the proportions at baseline.
Further warnings and precautions The efficacy and safety of MabThera in the treatment of autoimmune diseases other than
rheumatoid arthritis have not been investigated.
No data are available for patients with severe pulmonary disease. Caution should therefore
be exercised when MabThera is used in these patients.
No data are available for patients with anemia (Hb <8.5 g/dl) or neutropenia (neutrophil
count <1,500/μl).

At present few data are available on possible drug interactions involving MabThera. In
particular, interactions of rituximab in combination with chemotherapy (e.g. CHOP, CVP)
have not been investigated.
Neither coadministration of fludarabine or cyclophosphamide with rituximab nor
coadministration of methotrexate with rituximab has any effect on the pharmacokinetics of
the individual components.
Patients with human antimurine antibody (HAMA) or human antichimeric antibody
(HACA) titres may develop allergic or hypersensitivity reactions when treated with other
diagnostic or therapeutic monoclonal antibodies.
No pharmacokinetic or pharmacodynamic data are available on concomitant use of
MabThera and TNF inhibitors. TNF inhibitors should not be administered for at least 8
weeks after completion of treatment with MabThera.

Pregnancy Categore C.
IgG immunoglobulins are known to cross the placental barrier. Because of the long
retention time of MabThera in patients with B-cell depletion, women of child-bearing age
should employ effective contraceptive methods during treatment with MabThera and for
up to 12 months thereafter.
No fetal damage was found in reproductive toxicology studies in monkeys. B-cell-depleted
populations were found in the postnatal phase in neonatal offspring of dams that had been
exposed to MabThera during pregnancy. No studies of B-cell populations in human
neonates after maternal exposure to MabThera have been performed. There are no

adequate and well-controlled data from studies in pregnant women, however, transient B-
cell depletion and lymphocytopenia have been observed in some infants born to mothers

exposed to rituximab during pregnancy. For these reasons MabThera must not be
administered to pregnant women unless clearly necessary. Women of child-bearing age
should employ effective contraceptive methods during treatment with MabThera and for
up to 12 months thereafter.
Lactation
It is not known whether rituximab is excreted in human milk. Given, however, that
maternal IgG enters breast milk and that MabThera has been found in the milk of lactating
monkeys, women who are being treated with MabThera should not breast-feed.

No studies have been performed on the effects of MabThera on the ability to drive or to
operate machines. The pharmacological action and the undesirable effects observed to date
do not suggest the likelihood of any such effects. Nevertheless, the influence of
premedication with antihistamines should be noted. After infusion reactions the patient’s
condition should be allowed to stabilise before the patient drives vehicles or operates
machines.

Experience from clinical studies in NHL
The frequencies of adverse drug reactions reported with MabThera either as monotherapy
or in combination with chemotherapy are summarised below. Within each frequency
category adverse drug reactions are listed in decreasing order of severity. Frequencies are
defined as very common (1/10), common (1/100 to <1/10), occasional (1/1,000 to
<1/100), rare (1/10,000 to <1/1,000) or very rare (<1/10,000).
The adverse drug reactions of all degrees of severity listed below are based on data from
studies with approximately 2,300 patients in which MabThera was administered either as
monotherapy or in combination with chemotherapy.
Infections and infestations
Very common: bacterial infections, viral infections, bronchitis.
Common: sepsis, pneumonia, febrile infection, herpes zoster, respiratory tract infection,
fungal infections, infections of unknown etiology, sinusitis, hepatitis B.
Isolated cases of infection with cytomegalovirus, herpesvirus, JC virus-associated
progressive multifocal leukoencephalopathy (see Warnings and precautions), hepatitis C
and fulminant hepatitis.
Blood and lymphatic system disorders
Very common: neutropenia (which may be prolonged and/or late in onset after completing
a treatment cycle), leukopenia, febrile neutropenia, thrombocytopenia.
Common: anemia, pancytopenia, granulocytopenia.
Occasional: coagulation disorders, aplastic anemia, hemolytic anemia, lymphadenopathy.
Immune system disorders
Very common: angioedema.
Common: hypersensitivity reactions.
Very rare: vasculitis.
Isolated cases of serum sickness-like reactions.
Metabolic and nutritional disorders
Common: hyperuricemia, hyperglycemia, weight loss, elevated LDH, hypocalcemia.

Psychiatric disorders
Occasional: depression, nervousness.
Nervous system disorders
Common: paresthesia, hypoesthesia, restlessness, insomnia, vasodilatation, dizziness,
anxiety.
Occasional: dysgeusia.
Isolated cases of peripheral neuropathy, sensory disturbances, facial nerve palsy.
There have been post-marketing reports of cases of posterior reversible encephalopathy
syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS).
Eye disorders
Common: lacrimation disorders, conjunctivitis.
Isolated cases of severe vision loss.
Ear and inner ear disorders
Common: tinnitus, ear pain.
Isolated cases of hearing loss.
Cardiac disorders
Common: myocardial infarction, arrhythmia, atrial fibrillation, tachycardia, heart failure.
Occasional: left ventricular failure, supraventricular tachycardia, ventricular tachycardia,
angina pectoris, myocardial ischemia, bradycardia.
Vascular disorders
Common: hypertension, orthostatic hypotension, hypotension.
Respiratory disorders
Common: bronchospasm, chest pain, dyspnea, cough, rhinitis.
Occasional: asthma, bronchiolitis obliterans, respiratory failure, hypoxia.
Rare: pulmonary edema.
Very rare: death due to respiratory failure.
Frequency unknown: interstitial lung disease, some cases of which may be fatal.
Gastrointestinal disorders
Very common: nausea.
Common: vomiting, diarrhea, abdominal pain, dysphagia, stomatitis, constipation,
dyspepsia, anorexia, throat irritation.
Occasional: abdominal enlargement.
Isolated cases of gastrointestinal perforation or obstruction.
Hepatobiliary disorders
Very rare: hepatitis.
Skin and subcutaneous tissue disorders
Very common: pruritus, skin rash, alopecia.

Common: urticaria, alopecia, sweating, night sweats.
Isolated cases of skin diseases such as severe bullous skin reactions, including fatal cases
of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS).
Musculoskeletal disorders
Common: myalgia, arthralgia, back pain, neck pain, pain.
Renal disorders
Very rare: acute renal failure (in association with tumour lysis syndrome).
General disorders and administration site reactions
Very common: fever (48.3%), chills (31.3%), asthenia, headache.
Common: fatigue, shivering, tumour pain, flushing, malaise, cold syndrome, peripheral
edema, facial edema.
Occasional: pain at the infusion site.
Investigations
Very common: decreased IgG levels.

Experience from clinical studies in rheumatoid arthritis and ANCA-associated
vasculitis
Frequencies are defined as very common (1/10), common (1/100 to <1/10), occasional
(1/1,000 to <1/100), rare (1/10,000 to <1/1,000) or very rare (<1/10,000).
Infections and infestations
Very common: upper respiratory tract infections, urinary tract infections, infections
(61.6%).
Common: pneumonia, bronchitis, sinusitis, gastroenteritis, tinea pedis.
Isolated cases of progressive multifocal leukoencephalopathy (PML), serum sickness-like
reactions and reactivation of hepatitis B infection.
Blood and lymphatic system disorders
Very common: anemia (16.2%), leukopenia (10.1%).
Events of neutropenia were observed with MabThera treatment, the majority of which
were transient and mild or moderate in severity. Neutropenia can occur several months
after the administration of MabThera.
In placebo-controlled clinical trials, 0.94% (13/1,382) of rituximab-treated patients and
0.27% (2/731) of placebo patients developed severe neutropenia.
Rare: Neutropenic events, including severe late-onset and persistent neutropenia, have
been reported in the post-marketing setting, some of which were associated with fatal
infections.

In patients with ANCA-associated vasculitis, 24% of those in the rituximab group and 23%
of those in the cyclophosphamide group developed grade 3 or greater neutropenia. The
effect of multiple rituximab treatment cycles on the development of neutropenia in patients
with ANCA-associated vasculitis has not been studied in clinical trials.
The safety and efficacy of MabThera have not been studied in pediatric patients.
Hypogammaglobulinemia has been observed in pediatric patients treated with MabThera;
some cases were serious, requiring long-term immunoglobulin replacement therapy. The
consequences of long-term B lymphocyte deficiency in pediatric patients are unknown.
Immune system disorders
Very common: infusion reactions (12.1%).
Common: hypersensitivity reactions.
Occasional: generalised edema, bronchospasm, wheezing, laryngeal edema, angioneurotic
edema, generalised pruritus, anaphylaxis, anaphylactoid reaction.
Rare: anaphylactic reactions, laryngeal edema, angioedema.
Very rare: severe infusion-related reactions with fatal outcome have been reported in the
post-marketing setting.
Hypogammaglobulinemia (IgM, IgG or IgA below the normal range) has been observed in
RA patients and in ANCA-associated vasculitis.
Metabolic and nutritional disorders
Common: hypercholesterolemia, hot flushes.
Psychiatric disorders
Very common: insomnia (14.1%).
Common: depression, anxiety.
Nervous system disorders
Very common: headaches (17.2%).
Common: migraine, paresthesia, dizziness, sciatica.
Vascular disorders
Very common: hypertension (12.1%).
Common: hypotension.
Respiratory disorders
Very common: cough (13.1%), epistaxis (11.1%), dyspnea (10.1%).
Rare: bronchospasm, wheezing.

Gastrointestinal disorders
Very common: nausea (18.2%), diarrhea (17.2%).
Common: dyspepsia, upper abdominal pain, gastroesophageal reflux, mouth ulcers.
Skin and subcutaneous tissue disorders
Very common: skin rash (10.1%).
Common: urticaria, alopecia.
Rare: pruritus.
Isolated cases of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS),
some of which were fatal, have been reported in the post-marketing setting.

Musculoskeletal system
Very common: muscle spasms (17.2%), arthralgia (13.1%).
Common: muscle pain, osteoarthritis, bursitis.
General disorders and administration site reactions
Very common: peripheral edema (16.2%), fatigue (13.1%).
Investigations
Very common: elevated ALT levels (13.1%).
General
Common: asthenia, chills.

No experience with overdosage is available from clinical trials in humans. However, single
doses higher than 1,000 mg have not been tested in controlled clinical studies.
The highest dose tested to date in patients with chronic lymphatic leukemia was 5 g. No
additional safety signals were identified. In the event of overdosage the infusion should be
stopped or reduced immediately and the patient closely monitored. In patients with B-cell
depletion the blood count should be checked regularly and attention paid to the increased
risk of infection.

ATC code: L01XC02
Mechanism of action
Rituximab is a chimeric mouse/human monoclonal antibody that binds specifically to the

transmembrane antigen CD20. This antigen is located on pre-B- and mature B-
lymphocytes, but not on hemopoietic stem cells, pro-B-cells, normal plasma cells or other

normal tissue. The antigen is expressed on >95% of all cells of B-cell non-Hodgkin’s
lymphomas (NHLs). Following antibody binding, CD20 is not internalised or shed from
the cell membrane into the environment. CD20 does not circulate in the plasma as a free 

antigen and thus does not compete for antibody binding. Studies conducted to date have
shown no connection between the intensity of CD20 expression on malignant cells and
therapeutic response.
Rituximab binds to the CD20 antigen on B-lymphocytes and causes B-cell lysis. Possible

mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-
dependent cellular cytotoxicity (ADCC) and induction of apoptosis.

Peripheral B-cell counts declined below normal following the first dose of MabThera. In
patients treated for hematological malignancies, B-cell recovery began within 6 months of
completing therapy and generally returned to normal levels within 12 months after the end
of treatment. In rheumatoid arthritis patients, the duration of B-cell depletion was variable.
The majority of patients received a further treatment before complete B-cell repletion. In
ANCA-associated vasculitis patients, peripheral blood CD19 B-cells declined after the first
two infusions of rituximab to below 10 cells/μl and remained at this level in most patients
for up to 6 months.
Of 67 patients tested for human antimouse antibody (HAMA), none proved positive. Of
356 patients with non-Hodgkin’s lymphoma tested for human antichimeric antibody
(HACA), 4 (1.1%) proved positive.
Of 1,039 patients with rheumatoid arthritis tested for human antichimeric antibodies
(HACA), 96 (9.2%) proved positive. The occurrence of HACA in these patients was not
associated with any clinical deterioration or with an increased risk for reactions to
subsequent infusions.
Out of 99 ANCA-associated vasculitis patients treated with rituximab, a total of 23 (23%)
were HACA-positive after 18 months. The clinical relevance of HACA development in
patients treated with rituximab is unclear.
Finally, in vitro studies have demonstrated that rituximab sensitises drug-resistant human
B-cell lymphoma lines to the cytotoxic effects of some chemotherapeutic agents.

Clinical efficacy
Non-Hodgkin’s lymphoma
Monotherapy

In the pivotal study, 166 patients with relapsed or chemoresistant low-grade or follicular B-
cell NHL received 375 mg/m2

of MabThera as an intravenous infusion once weekly for 4
weeks. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48%
(95% confidence interval [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 international working
formulation (IWF) B, C and D histological subtypes compared to the IWF A subtype (58%
vs 12%), higher in patients whose largest lesion was <5 cm in diameter than in those with
diameters >7 cm (53% vs 38%), and higher in patients with chemosensitive relapse
compared to those with chemoresistant relapse (defined as duration of response <3 months;
50% vs 22%). The ORR in patients with a previous autologous bone marrow transplant

(ABMT) was 78% vs 43% in those without. Neither age, sex, lymphoma grade, initial
diagnosis, presence or absence of a high tumour burden, normal or elevated LDH nor the
presence of extranodal disease had a statistically significant effect on response to
MabThera.
Combination with CVP
In a randomised open study a total of 321 treatment-naive patients with low-grade or
follicular B-cell NHL received CVP chemotherapy (cyclophosphamide 750 mg/m2
body

surface area, vincristine 1.4 mg/m2

body surface area up to a maximum of 2 mg on day 1

and prednisolone 40 mg/m2

body surface area/day on days 1–5) every 3 weeks for 8

treatment cycles or MabThera 375 mg/m
2
body surface area in combination with CVP
(R-CVP). MabThera was administered on day 1 of each treatment cycle. R-CVP performed
significantly better than CVP in terms of the primary endpoint (time to ‘treatment failure’,
defined as progression, relapse after response, initiation of new lymphoma therapy, no
response after 4 cycles, death): 25.9 months versus 6.7 months, p<0.0001).
Induction therapy and subsequent maintenance therapy in previously untreated patients
In a prospective open international phase III multicentre study 1,193 patients with
previously untreated advanced follicular lymphoma received induction therapy with
R-CHOP (N=881), R-CVP (N=268) or R-FCM (N=44) according to the investigating
physician’s choice. In total 1,078 patients responded to the induction therapy (ORR 99%);
of these 1,018 were randomised and allocated to MabThera maintenance therapy (N=505)
or observation (N=513).
The two treatment groups were well balanced in pretreatment demographics and disease
status. MabThera maintenance therapy consisted of a single infusion of MabThera
375 mg/m2

body surface area every 2 months until disease progression or for a maximum

of 2 years.
After a median 25 months follow-up from randomisation MabThera maintenance therapy
in patients with previously untreated follicular NHL achieved clinically relevant and
statistically significant improvement in the primary endpoint – investigator evaluation of
progression-free survival (PFS) – vs patients without maintenance therapy. The
improvement in PFS was confirmed by an independent review committee (IRC).
The significant benefit of MabThera maintenance therapy was also observed in the
secondary endpoints of event-free survival (EFS) and overall response rate (ORR)
(Table 1).
Table 1. Maintenance phase (25 months median follow-up)
Efficacy parameters Observation
(N=513)

Rituximab
(N=505)

Log-rank
p value

Risk reduction

Primary efficacy
PFS (median) NE NE <0.0001 50%

Secondary efficacy
EFS (median) 37.8 months NE <0.0001 46%
OS (median) NE NE 0.7246 11%
ORR* 55.0% 74.0% <0.0001 [odds ratio = 2.33]
* At end of maintenance therapy/observation
PFS = progression-free survival; EFS = event-free survival; OS = overall survival; ORR = overall response rate; NE =
not estimable at clinical cut-off
The benefit of MabThera maintenance treatment was confirmed across all study subgroups
including sex (male, female), age (<60 years, ≥60 years), FLIPI score (1, 2 or 3) and
induction treatment (R-CHOP, R-CVP or R-FCM), regardless of the quality of response to
induction treatment (CR or PR).
Induction and maintenance treatment in patients with relapsed or refractory disease
In an open, international, prospective multicentre phase III study, 465 patients with
relapsed/treatment-resistant follicular non-Hodgkin’s lymphoma were randomised in a first
phase to induction treatment with six cycles of CHOP (cyclophosphamide, doxorubicin,
vincristine, prednisone; N=231) or MabThera plus CHOP (R-CHOP, N=234). The two
treatment groups were well balanced in pretreatment demographics and disease status. In
total, 334 patients who had achieved complete or partial remission after induction therapy

were randomised in a second phase to MabThera maintenance therapy (N=167) or follow-
up (N=167). MabThera maintenance therapy consisted of a single infusion of MabThera

375 mg/m2

body surface area every 3 months until disease progression or for a maximum

of 2 years.
Table 2. Induction phase (31 months median follow-up)

CHOP R-CHOP p value

Primary efficacy parameters

ORR 74% 87% 0.0003
CR 16% 29% 0.0005
PR 58% 58% 0.9449

Secondary efficacy parameters

OS (median) NR NR 0.0508
PFS (median) 19.4 months 33.2 months 0.0001

NR = not reached; ORR = overall reponse rate; CR = complete response; PR = partial response; OS = overall survival;
PFS = progression-free survivalMedian follow-up for patients randomised in the maintenance
phase of the study was 28 months. MabThera maintenance therapy caused a clinically
relevant and statistically significant improvement of the primary endpoint, progression-free
survival (PFS; time from maintenance phase randomisation to relapse, disease progression
or patient death), compared to follow-up alone (p<0.0001, log-rank test). Median PFS in
the MabThera group was 42.2 months vs 14.3 months in the follow-up group. Cox
regression analysis showed that MabThera maintenance therapy reduced the risk of disease
progression or patient death by 61% compared to follow-up (95% Cl: 45%–72%). Kaplan-

Meier-estimated PFS rates after 12 months were 78% with MabThera maintenance therapy
compared to 57% in the follow-up group. Analysis of overall survival confirmed the
significant benefit of MabThera maintenance therapy over follow-up (p=0.0039, log-rank
test). MabThera maintenance therapy reduced the risk of death by 56% (95% Cl: 22%–
75%).
Median time to new lymphoma therapy was significantly longer with MabThera
maintenance therapy than with follow-up alone (38.8 months vs 20.1 months, p<0.0001,
log-rank test). The risk of having to institute new treatment was halved (95% Cl: 30%–
64%). In patients with CR or CRu as their best response to induction therapy, MabThera
maintenance therapy significantly prolonged median disease-free survival (DFS) compared
to follow-up (53.7 months vs 16.5 months, p=0.0003, log-rank test; table 3). The risk of
relapse in CR patients was reduced by 67% (95% Cl: 39%–82%).
Table 3. Maintenance phase (28 months median follow-up)
Efficacy parameters Kaplan-Meier estimate of median time to event (months)

Follow-up
(N=167)

MabThera
(N=167)

Log-rank test
p value
Progression-free survival (PFS) 14.3 42.2 <0.0001
Overall survival NR NR 0.0039
Time to new lymphoma therapy 20.1 38.8 <0.0001
Disease-free survivala

16.5 53.7 0.0003

NR = not reached; a

applies only to patients achieving CR
Diffuse large B-cell non-Hodgkin’s lymphoma
In a randomised open study a total of 399 previously untreated elderly patients (aged 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 prednisone 40 mg/m2

/day on days 1–5) every 3 weeks for

eight treatment cycles, or MabThera 375 mg/m2

plus CHOP (R-CHOP). MabThera was
administered on day 1 of the treatment cycle. Efficacy was analysed in all randomised
patients (CHOP: N=197; R-CHOP: N=202) over a (median) follow-up of approximately
31 months. The two treatment groups were well balanced in pretreatment demographics
and disease status. The final analysis confirmed that R-CHOP significantly prolonged
(p=0.0001) the duration of the primary efficacy endpoint, event-free survival (events:

death, relapse, lymphoma progression or institution of new lymphoma treatment). Kaplan-
Meier estimates of median event-free survival were 35 months in the R-CHOP treatment

group compared to 13 months in the CHOP treatment group. This was equivalent to a risk
reduction of 41%. At 24 months, estimates for overall survival were 68.2% in the R-CHOP
group compared to 57.4% in the CHOP group. Subsequent analysis at 60 months
confirmed the benefit of R-CHOP over CHOP: the overall survival rate after R-CHOP was
62.4% compared with 50.8% in the CHOP group (p=0.0071), representing a survival risk
reduction of 32%.

Analysis of all secondary endpoints (response rates, PFS, DFS, duration of response)
confirmed the benefit of R-CHOP treatment over CHOP. The CR rate after treatment
cycle 8 was 76.2% in the R-CHOP group compared to 62.4% in the CHOP group
(p=0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by
51%.
In all patient subgroups (sex, age, age-adjusted international prognostic index [IPI], Ann
Arbor stage, Eastern Cooperative Oncology Group [ECOG], β2-microglobulin, LDH,
albumin, B-symptoms, high tumour burden, extranodal sites, bone marrow involvement),
the risk ratios for event-free survival and overall survival (R-CHOP vs CHOP) were less

than 0.83 and 0.95. R-CHOP treatment correlated with improved outcome for both high-
and low-risk patients according to age-adjusted IPI.

Chronic lymphocytic leukemia (CLL)
In two open-label randomised trials a total of 817 previously untreated patients and 552
patients with relapsed/refractory CLL were randomised to receive either FC chemotherapy
(fludarabine 25 mg/m2

, cyclophosphamide 250 mg/m2

, days 1–3) every 4 weeks for 6
cycles or MabThera in combination with FC (R-FC). MabThera was administered in the
first cycle at a dosage of 375 mg/m2

one day before chemotherapy and at a dosage of

500mg/m2

on day 1 of each subsequent treatment cycle.

In the first-line study, median progression-free survival (primary endpoint) was 42.8
months in the R-FC group and 32.5 months in the FC group (p<0.0001). The analysis of
overall survival showed a survival advantage in the R-FC arm (p=0.0427).
The overall response rate was 86.1% vs 72.7%, with complete response (CR) in 36.0% vs
17.2% (p<0.0001).
In the relapsed/refractory disease study, 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). Median overall survival has not yet been reached in the R-FC arm and is 51.9
months in the FC arm.
The overall response rate was 69.9% vs 58.0%, with complete response (CR) in 24.3% vs
13.0% (p<0.0007).
Rheumatoid arthritis
The efficacy and safety of MabThera in the treatment of rheumatoid arthritis were
demonstrated in three randomised, controlled, double-blind, multicentre studies.
Study 1 (WA17042) was a phase III double-blind comparative study with 517 patients who
had failed to respond adequately to, or had not tolerated, one or more treatments with TNF
inhibitors. In order to be included in the study, patients had to suffer from severe active
rheumatoid arthritis that had been diagnosed in accordance with the criteria of the
American College of Rheumatology (ACR). The primary endpoint was the percentage of
patients who had achieved an ACR 20 response after 24 weeks. On two occasions
separated by an interval of 15 days the patients received an i.v. infusion of 1,000 mg
MabThera, in each case after infusion of 100 mg methylprednisolone. All patients also

received oral methotrexate (10–25 mg/week) plus oral prednisone 60 mg from day 2 to day
7 and 30 mg from day 8 to day 14 after the first infusion.
Patients were followed beyond week 24 for long-term endpoints, including radiographic
assessment at 56 weeks. During this time patients may have received further courses of
rituximab under an open-label extension study protocol.
Study 2 (WA17043) was a randomised, controlled, double-blind, multifactorial (3 × 3),
double-dummy phase II study comparing two dosage levels of rituximab (2 × 1,000 mg
and 2 × 500 mg). Rituximab was administered with or without infused glucocorticoid
therapy (one of two therapeutic schemes) in combination with weekly methotrexate
administration to patients who suffered from active rheumatoid arthritis and had failed to
respond to treatment with at least 1–5 DMARDs other than methotrexate.
Study 3 (WA16291) was a controlled, double-blind, double-dummy study assessing
rituximab as a single agent and in combination with cyclophosphamide or methotrexate in
patients with active rheumatoid arthritis who had failed to respond to treatment with one or
more DMARDs.
Patients given weekly methotrexate (10–25 mg per week) served as a comparator group in
all three studies.
Effect on disease activity
In all three studies treatment with 2 × 1,000 mg rituximab resulted in a significant increase
in the proportion of patients who experienced an improvement of at least 20% in their
ACR value compared to treatment with methotrexate alone (Table 4). The therapeutic
effect was similar in all patients and was independent of rheumatoid factor status, age, sex,
body surface area, race, number of previous treatments and disease status.
A clinically and statistically significant improvement was also found in all the individual
components of the ACR response (tender and swollen joints, global assessment by patient
and physician, HAQ disability index score, pain assessment and C-reactive protein
[mg/dl]).
Table 4. ACR response rates after 24 weeks in the various studies (ITT population)

ACR response Placebo + MTX Rituximab + MTX
2 × 1,000 mg

Rituximab + MTX
2 × 500 mg

Study 1
(WA17042)1

N=201
RF-positive and
-negative patients
N=298
RF-positive and
-negative patients
−

ACR 20 36 (18%) 153 (51%)3

−

ACR 50 11 (5%) 80 (27%)3

ACR 70 3 (1%) 37 (12%)3

−

Study 2
(WA17043)2

N=143
RF-positive and
-negative patients
N=185
RF-positive and
-negative patients
N=123
RF-positive
patients

ACR 20 45 (31%) 96 (52%)4

68 (55%)4

ACR 50 19 (13%) 61 (33%)4

40 (33%)4

ACR 70 6 (4%) 28 (15%)4

16 (13%)5

Study 3
(WA16291)2

N=40
RF-positive
patients

N=40
RF-positive
patients

−

ACR 20 15 (38%) 28 (70%)5

−

ACR 50 5 (13%) 17 (43%)5

−

ACR 70 2 (5%) 9 (23%)5

−

1
Inadequate response to TNF inhibitors
2
Inadequate response to one or more DMARDs
3
p0.0001; 4
p0.001; 5
p<0.05
RF = rheumatoid factor

In study 3 (WA16291) the efficacy of rituximab as a single agent was assessed in an
additional treatment arm. This showed an ACR 20 response rate of 65% compared to 38%
with methotrexate alone (p=0.025).
The 28-joint disease activity score (DAS28) fell significantly more in the patients treated
with rituximab than in those treated with methotrexate alone. Significantly more patients
achieved a moderate to good European league against rheumatism (EULAR) response with
rituximab than with methotrexate alone (Table 5).

Table 5. DAS and EULAR response rates after 24 weeks in the various studies

(ITT population)

Placebo + MTX Rituximab + MTX
2 × 1,000 mg

Rituximab + MTX
2 × 500 mg

Study 1 (WA17042)1 N=201
RF-positive and
-negative patients

N=298
RF-positive and
-negative patients
−

DAS28 change (mean [standard
deviation])

–0.4 (1.2) –1.9 (1.6)* −

EULAR response (%)
None
Moderate
Good

78%
20%
2%

35%
50%*
15%

−

Study 2 (WA17043)2 N=143
RF-positive and
-negative patients

N=185
RF-positive and
-negative patients

N=123
RF-positive patients

DAS28 change (mean [standard
deviation])

–0.8 (1.4) –2.0 (1.6) –1.9 (1.4)

EULAR response
None
Moderate
Good

61%
35%
4%

37%
40%
23%

28%
59%
14%

Study 3 (WA16291)2 N=40

RF-positive patients
N=40
RF-positive patients
−

DAS change (mean [standard
deviation])

–1.3 (1.2) –2.6 (1.3)

Placebo + MTX Rituximab + MTX
2 × 1,000 mg

Rituximab + MTX
2 × 500 mg

EULAR response
None
Moderate
Good

50%
45%
5%

18%
63%
20%

−

1
Inadequate response to TNF inhibitors
2
Inadequate response to one or more DMARDs
* p<0.0001; p values for studies 2 and 3 not calculated
RF = rheumatoid factor
Radiographic response
Study WA17042 conducted in TNF-IR patients receiving MabThera in combination with
methotrexate demonstrated significantly less radiographic progression at 56 weeks in
patients in the MabThera plus MTX group than in patients in the group receiving MTX
alone. A higher proportion of patients receiving MabThera also had no erosive progression
over 56 weeks (Table 6).
Inhibition of the rate of progressive joint damage was also observed in the long term.
Radiographic analysis at 2 years in study WA17042 demonstrated significantly reduced
progression of structural joint damage in patients receiving MabThera (2 × 1,000 mg) plus
MTX compared to MTX alone as well as a significantly higher proportion of patients with
no progression of joint damage over the 2-year period.
Table 6. Radiographic outcomes at 1 year in study WA17042 (MITT population)

Placebo + MTX

Rituximab + MTX
(2 × 1,000 mg)
Study WA17042 (TNF-IR) (N=184) (N=273)
Mean change from baseline:
Modified total Sharp score 2.31 1.00
Erosion score 1.32 0.59

Placebo + MTX

Rituximab + MTX
(2 × 1,000 mg)
Joint space narrowing score 0.99 0.41
Proportion of patients with no
radiographic change 46% 53%
Proportion of patients with no erosive
change 52% 61%

Effect on quality of life
The patients treated with rituximab reported an improvement in all patient-related results
(HAQ-DI, FACIT-F and SF-36 questionnaires, Tables 7 and 8). Compared to the patients
treated with methotrexate alone, the patients treated with rituximab showed a significant
reduction in the disability (HAQ-DI) and fatigue (FACIT-F) indexes and an improvement
in the physical-health and mental-health categories of the SF-36 questionnaire.

Table 7. Short Form Health Survey (SF-36): mean and categorical change from

baseline to week 24

Study 1 (WA17042) Study 2 (WA17043)
Placebo + MTX

N=197

Rituximab
+ MTX
N=294

Placebo
+ MTX
N=141

Rituximab
+ MTX
N=178

Mental health
Mean change
(standard
deviation)

1.3 (9.4) 4.7 (11.8) 1.8 (8.0) 3.2 (11.2)

p value* 0.0002
Improved 40 (20%) 111 (38%) 29 (21%) 60 (34%)
Unchanged 128 (65%) 144 (49%) 99 (70%) 90 (51%)
Worsened 29 (15%) 39 (13%) 13 (9%) 28 (16%)
p value* 0.0015
Physical health
Mean change
(standard
deviation)

0.9 (5.7) 5.8 (8.5) 1.96 (6.3) 6.1 (8.2)

p value* <0.0001
Improved 25 (13%) 141 (48%) 37 (26%) 88 (49%)
Unchanged 158 (80%) 136 (46%) 92 (65%) 81 (46%)
Worsened 14 (7%) 17 (6%) 12 (9%) 9 (5%)
p value* <0.0001
* The data from study 2 (WA17043) were not analysed.
Mental health change category: change >6.33 = improved,
–6.33 ≤ =change <6.33 = unchanged, change <–6.33 = worsened.

Physical health change category: change >5.42 = improved,
–5.42 ≤=change <5.42 = unchanged, change <–5.42 = worsened.
Table 8. HAQ and FACIT-F response at week 24 in study 1 (WA17042)
Response at week 24:
Change from baseline value

Placebo + MTX1
N=201
Mean (standard
deviation)

Rituximab + MTX1
N=298
Mean (standard
deviation)

p value

HAQ2

–0.1 (0.5) –0.4 (0.6) <0.0001

FACIT-F
3

–0.5 (9.8) –9.1 (11.3) <0.0001

1 Methotrexate
2 Health assessment questionnaire (HAQ)
3 Functional assessment of chronic illness therapy (FACIT-F)
At 24 weeks the proportion of patients in all three studies achieving clinically significant
improvement in HAQ-DI index (defined as a decrease of >0.25 in individual total score)
was greater with rituximab than with methotrexate alone.
Laboratory values
Approximately 10% of patients with rheumatoid arthritis tested positive for HACA in
clinical studies. The emergence of HACA in these patients was not associated with clinical
deterioration or with an increased risk of reactions to subsequent infusions. The presence
of HACA may be associated with worsening of infusion or allergic reactions after the
second infusion of subsequent courses. Failure to deplete B-cells after further treatment
courses has been observed rarely.
In one of the studies 15 of 308 patients (4.8%) treated with MabThera and 8 of 209 patients
(3.8%) treated with methotrexate alone tested negative for antinuclear antibodies (ANA)
on day 1 and positive at week 16 and/or week 24. The profile of adverse events in these
patients provided no evidence of incident autoimmune disease.
In rheumatoid factor (RF) positive patients a marked decrease (range: 45%–64%) in RF
concentrations was observed in all three studies after MabThera treatment.
The total plasma immunoglobulin concentration, total lymphocyte count and leukocyte
count generally remained within normal limits after treatment with MabThera apart from a

transient fall in leukocyte count in the first 4 weeks after treatment. Titres of antigen-
specific IgG antibodies against mumps, rubella, varicella, tetanus toxoid, influenza and

Streptococcus pneumoniae remained stable for 24 weeks in patients with rheumatoid
arthritis after treatment with MabThera.
The effect of rituximab on various biomarkers was studied in patients included in study 3
(WA16291). This substudy examined the effect of a single treatment cycle of rituximab on 

biochemical marker concentrations. These included inflammatory markers (interleukin-6,
C-reactive protein, serum amyloid A protein and S100 protein isotypes A8 and A9),
autoantibodies (RF and anticyclic citrullinated peptide), immunoglobulin production and
bone turnover (osteocalcin and type 1 collagen N-terminal propeptide [P1NP]). Treatment
with rituximab – as both monotherapy and combination therapy with methotrexate or
cyclophosphamide – significantly decreased inflammatory marker concentrations in the
first 24 weeks of follow-up compared to methotrexate alone. The concentration of bone
turnover markers osteocalcin and P1NP increased significantly in the groups taking
rituximab compared to those taking methotrexate alone.
ANCA-associated vasculitis
A total of 197 patients with severe active ANCA-associated vasculitis (AAV) were

enrolled and treated in an active-controlled, randomised, double-blind, multicentre non-
inferiority study. The patients were 15 years of age or older and had been diagnosed with

either severe active granulomatosis with polyangiitis, also known as Wegener’s
granulomatosis (75% of patients) or microscopic polyangiitis (24% of patients) according
to the criteria of the Chapel Hill consensus conference (in 1% of patients the type of
ANCA-associated vasculitis was unknown).
Patients were randomised in a 1:1 ratio to receive treatment with either oral
cyclophosphamide (2 mg/kg body weight/day) for 3–6 months followed by azathioprine or
MabThera (375 mg/m2

) once weekly for 4 weeks. In both treatment arms patients received
intravenous pulse therapy with methylprednisolone 1,000 mg daily (or another
glucocorticoid at an equivalent dose) for 1 to 3 days followed by oral prednisone (1 mg/kg
body weight/day, not exceeding 80 mg/day). The prednisone had to have been tapered to
zero within 6 months of starting the study treatment.
The primary endpoint was the achievement of complete remission after 6 months, defined
by a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of
0 and the discontinuation of glucocorticoid therapy. The predefined non-inferiority margin
for the difference between treatments was 20%. The study showed at least equivalent
efficacy (non-inferiority) by MabThera compared to cyclophosphamide with respect to
complete remission after 6 months (Table 9). In addition, on the basis of historical control
data, the complete remission rate in the MabThera treatment arm was significantly higher
than the estimated complete remission rate in patients with severe ANCA-associated
vasculitis who were untreated or treated with glucocorticoids only.
Efficacy was observed in both patients with newly diagnosed ANCA-associated vasculitis
and patients with recurrent disease.

Table 9. Percentage of patients achieving complete remission after 6 months (ITT

population)
MabThera
(N=99)

Cyclophosphamide
(N=98)

Treatment difference
(MabThera – cyclophosphamide)

Rate 63.6% 53.1% 10.6%
95.1% CI (54.1%, 73.2%) (43.1%, 63.0%) (3.2%, 24.3%)

In the RAVE study patients in the rituximab treatment group received no maintenance
therapy whereas those in the cyclophosphamide group received azathioprine maintenance
therapy after the induction of remission. Maintenance of efficacy in the RAVE study was
assessed after 12 and 18 months; the most important secondary endpoints of the study were
complete remission after 12 and 18 months. In the rituximab group 44% of patients were in
complete remission after 6 and 12 months and 38% after 6, 12 and 18 months. Of the
patients treated with cyclophosphamide (followed by azathioprine), 38% were in complete
remission after 6 and 12 months and 31% after 6, 12 and 18 months.

The mean Cmax following the fourth infusion of 375 mg/m2 was 486 μg/ml (range 77.5 to
996.6 μg/ml). Following the intravenous administration of 500 and 1,000 mg doses of
rituximab on two occasions two weeks apart, mean Cmax values were 183 μg/ml (range
81.8 to 279 μg/ml) and 370 μg/ml (range 212 to 637 μg/ml), respectively.
Distribution: The mean steady-state distribution volume was 4.6 l (range 1.7 to 7.51 l).
Elimination: Like all proteins, rituximab is broken down in the liver. The estimated mean
terminal elimination half-life of rituximab is 20.8 to 24 days (range 6.1 to 52 days).
Tumour mass has an influence on specific clearance.
Special populations
Age, sex, ethnicity and WHO performance status had no influence on the pharmacokinetics
of rituximab.
No pharmacokinetic data are available in patients with hepatic or renal impairment.

Mutagenicity and carcinogenicity have not been studied. There have been no preclinical
studies of the combination of MabThera and methotrexate.
No evidence of rituximab-induced fetotoxicity was observed in developmental toxicity
studies in cynomolgus monkeys treated with doses up to 100 mg/kg body weight (from
days 20 to 50 of gestation). However, pharmacological dose-dependent B-cell depletion
was observed in the fetal lymphoid tissue. This persisted after birth and was associated
with decreased IgG concentrations in the newborns concerned. B-cell counts reverted to normal in these animals within six months after birth and did not impair the response to
immunisation.

Additional information

No incompatibilities between MabThera and polyvinylchloride or polyethylene bags or
infusion sets have been observed.
MabThera may only be mixed with the solutions listed under Instructions for handling and
disposal.

Influence on diagnostic tests
Possible effects on response to vaccines and on diagnostic tests based on the demonstration
of antibodies have not been investigated.

Store vials in a refrigerator (at 2–8°C). Store the container inside the outer package in order
to protect the contents from light.
Keep medicines out of reach of children.
The prepared infusion solution of MabThera is physically and chemically stable for 24
hours at 2–8°C and for 12 hours at 15–25°C. From a microbiological point of view, the

prepared infusion solution should be used immediately. If not used immediately, post-
preparation storage times and conditions prior to use are the responsibility of the user and

should normally not exceed 24 hours at 2–8°C unless dilution has taken place in controlled
and validated aseptic conditions.

Packs

Vial of 10 ml (10 mg/ml) 2
Vial of 50 ml (10 mg/ml)

MabThera is a clear, colourless liquid presented in sterile, single-use, preservative- and
pyrogen-free rubber-stoppered vials.
Withdraw the required amount of MabThera under aseptic conditions and dilute in an
infusion bag containing sterile, non-pyrogenic, 0.9% aqueous saline solution or 5%
aqueous dextrose solution to a calculated rituximab concentration of 1 to 4 mg/ml. To mix
the solution, gently invert the bag to avoid foaming. As the product contains no
antimicrobial preservative or bacteriostatic agent, aseptic technique must be observed.
Parenteral medications should be inspected visually for particulate matter or discoloration
prior to administration.
Any unused medication remaining after the end of treatment or expiry of the product is to
be disposed of in accordance with applicable local regulations.