ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
MabThera 100 mg concentrate for solution for infusion
2.
Each ml contains 10 mg of rituximab.
Each single-use vial containing 100 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.
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion.
Clear, colourless liquid.
4.
MabThera is indicated in adults for the following indications:
Non-Hodgkin’s lymphoma (NHL)
MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicular
lymphoma in combination with chemotherapy.
MabThera maintenance therapy is indicated for the treatment of follicular lymphoma patients
responding to induction therapy.
MabThera 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.
MabThera 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)
MabThera in combination with chemotherapy is indicated for the treatment of patients with previously
untreated and relapsed/refractory chronic lymphocytic leukaemia. Only limited data are available on
efficacy and safety for patients previously treated with monoclonal antibodies including MabThera or
patients refractory to previous MabThera plus chemotherapy.
See section 5.1 for further information.
2
Rheumatoid arthritis
MabThera 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.
MabThera 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.
MabThera infusions should be administered under the close supervision of an experienced physician,
and in an environment where full resuscitation facilities are immediately available.
Posology
Non-Hodgkin’s lymphoma
Dosage adjustments during treatment
No dose reductions of MabThera are recommended. When MabThera is given in combination with
chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be
applied.
Follicular non-Hodgkin's lymphoma
Combination therapy
The recommended dose of MabThera in combination with chemotherapy for induction treatment of
previously untreated or relapsed/ refractory patients with follicular lymphoma is: 375 mg/m
2
body
surface area per cycle, for up to 8 cycles.
MabThera 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 MabThera used as a maintenance treatment for patients with previously
untreated follicular lymphoma who have responded to induction treatment is: 375 mg/m
2
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.
Relapsed/refractory follicular lymphoma
The recommended dose of MabThera used as a maintenance treatment for patients with
relapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m
2
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.
Monotherapy
Relapsed/refractory follicular lymphoma
The recommended dose of MabThera 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/m
2
body surface area, administered as an intravenous infusion once
weekly for four weeks.
For retreatment with MabThera monotherapy for patients who have responded to previous treatment
with MabThera monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is:
375 mg/m
2
body surface area, administered as an intravenous infusion once weekly for four weeks
(see section 5.1).
3
Diffuse large B cell non-Hodgkin's lymphoma
MabThera should be used in combination with CHOP chemotherapy. The recommended dosage is
375 mg/m
2
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 MabThera
have not been established in combination with other chemotherapies in diffuse large B cell non-
Hodgkin’s lymphoma.
Chronic lymphocytic leukaemia
Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start
of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL
patients whose lymphocyte counts are > 25 x 10
9
/L it is recommended to administer
prednisone/prednisolone 100 mg intravenous shortly before infusion with MabThera to decrease the
rate and severity of acute infusion reactions and/or cytokine release syndrome.
The recommended dosage of MabThera in combination with chemotherapy for previously untreated
and relapsed/refractory patients is 375 mg/m
2
body surface area administered on day 0 of the first
treatment cycle followed by 500 mg/m
2
body surface area administered on day 1 of each subsequent
cycle for 6 cycles in total. The chemotherapy should be given after MabThera infusion.
Rheumatoid arthritis
Patients treated with MabThera must be given the patient alert card with each infusion (see Annex
IIIA – Labelling).
A course of MabThera consists of two 1000 mg intravenous infusions. The recommended dosage of
MabThera 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. Retreatment
should be given at that time if residual disease activity remains, otherwise retreatment should be
delayed until disease activity returns.
Available data suggest that clinical response is usually achieved within 16 - 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.
Patients should receive treatment with 100 mg intravenous methylprednisolone to be completed 30
minutes prior to MabThera infusions to decrease the incidence and severity of infusion related
reactions (see method of administration).
First infusion of each course
The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in
50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
Second infusion of each course
Subsequent doses of MabThera can be infused at an initial rate of 100 mg/hr, and increased by
100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr.
Special populations
Paediatric use
The safety and efficacy of MabThera in children has not been established.
Elderly
No dose adjustment is required in elderly patients (aged >65 years).
4
Method of administration
Premedication with glucocorticoids should be considered if MabThera is not given in combination
with glucocorticoid-containing chemotherapy for treatment of non-Hodgkin’s lymphoma and chronic
lymphocytic leukaemia.
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and
diphenhydramine, should always be administered before each infusion of MabThera.
First infusion
The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in
50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
Subsequent infusions
Subsequent doses of MabThera can be infused at an initial rate of 100 mg/hr, and increased by
100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr.
The prepared MabThera 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 (section 4.8) usually respond to a reduction in the rate of
infusion. The infusion rate may be increased upon improvement of symptoms.
Hypersensitivity to the active substance or to any of the excipients or to murine proteins.
Active, severe infections (see section 4.4).
Patients in a severely immunocompromised state
Hypersensitivity to the active substance or to any of the excipients or to murine proteins.
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).
Progressive multifocal leukoencephalopathy
5
All patients treated with MabThera for rheumatoid arthritis must be given the patient alert card with
each infusion (see end of Annex IIIA - Labelling). The alert card contains important safety
information for patients regarding potential increased risk of infections, including progressive
multifocal leukoencephalopathy (PML).
Use of MabThera maybe associated with an increased risk of PML. 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, 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 MabThera 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 MabThera therapy may lead to similar stabilisation or improved outcome.
Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia
Infusion reactions
Patients with a high tumour burden or with a high number (≥25 x 10
9
/l) of circulating malignant cells
such as patients with CLL , who may be at higher risk of especially severe cytokine release syndrome,
should only be treated with extreme caution. These patients should be very closely monitored
throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for
the first infusion in these patients or a split dosing over two days during the first cycle and any
subsequent cycles if the lymphocyte count is still >25 x 10
9
/L.
Severe cytokine release syndrome
is characterised by severe dyspnea, 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, hyperphosphaetemia, 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.
Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with
MabThera (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
6
MabThera 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 glucocorticooids, should
be available for immediate use in the event of an allergic reaction during administration of MabThera.
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 MabThera infusion, consideration should be given to withholding
anti-hypertensive medicines 12 hours prior to the MabThera infusion.
Cardiac disorders
Angina pectoris, or cardiac arrhythmias
such as atrial flutter and fibrillation, heart failure and/or
myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a
history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.
Haematological toxicities
Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when
considering treatment of patients with neutrophils < 1.5 x 10
9
/l and/or platelet counts < 75 x 10
9
/l as
clinical experience in this population is limited
.
MabThera 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
MabThera therapy.
Infections
Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8).
MabThera 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 MabThera 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 MabThera 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 suggest that
MabThera treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus
(HBV) screening should be considered for high risk patients before initiation of treatment with
MabThera. Carriers of hepatitis B and patients with a history of hepatitis B should be closely
monitored for clinical and laboratory signs of active HBV infection during and for several months (up
to seven) following MabThera therapy.
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-
marketing use of MabThera in NHL and CLL (see section 4.8). The majority of patients had received
rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.
7
The safety of immunization with live viral vaccines, following MabThera therapy has not been studied
for NHL and CLL patients
and vaccination with live virus vaccines is not recommended. Patients
treated with MabThera may receive non-live vaccinations. However with non-live vaccines response
rates may be reduced. In a non-randomized study, patients with relapsed low-grade NHL who received
MabThera 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. 69% when assessed for >2-fold increase in antibody titer).
For CLL patients
similar results are assumable considering similarities between both diseases but that has not been
investigated in clinical trials.
Mean pre-therapeutic antibody titers against a panel of antigens (Streptococcus pneumoniae, influenza
A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with MabThera
Rheumatoid arthritis
Methotrexate (MTX) naïve populations
The use of MabThera is not recommended in MTX-naïve patients since a favourable benefit risk
relationship has not been established.
Infusion related reactions
MabThera is associated with infusion related reactions (IRR), which may be related to release of
cytokines and/or other chemical mediators. Premedication with intravenous glucocorticoid
significantly reduced the incidence and severity of these events and should be administered prior to
MabThera treatment (see section 4.2 and section 4.8).
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. The reactions reported
were usually reversible with a reduction in rate, or interruption, of MabThera infusion and
administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or
bronchodilators, and glucocorticoids if required. In most cases, the infusion can be resumed at a 50 %
reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.
Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline),
antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic
reaction during administration of MabThera.
There are no data on the safety of MabThera in patients with moderate heart failure (NYHA class III)
or severe, uncontrolled cardiovascular disease. In patients treated with MabThera, 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,
the risk of cardiovascular complications resulting from infusion reactions should be considered before
treatment with MabThera and patients closely monitored during administration. Since hypotension
may occur during MabThera infusion, consideration should be given to withholding anti-hypertensive
medications 12 hours prior to the MabThera infusion.
Infections
Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8).
MabThera 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 MabThera 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 MabThera.
8
Patients reporting signs and symptoms of infection following MabThera therapy should be promptly
evaluated and treated appropriately. Before giving a subsequent course of MabThera 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 MabThera for the treatment of rheumatoid arthritis and 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 fatal hepatitis B reactivation have been reported (see non-Hodgkin’s
lymphoma). Reactivation of hepatitis B infection has also been very rarely reported in RA patients
receiving MabThera.
Immunization
Physicians should review the patient’s vaccination status and follow current immunization guidelines
prior to MabThera therapy. Vaccination should be completed at least 4 weeks prior to first
administration of MabThera.
The safety of immunization with live viral vaccines following MabThera therapy has not been studied.
Therefore vaccination with live virus vaccines is not recommended whilst on MabThera or whilst
peripherally B cell depleted.
Patients treated with MabThera may receive non-live vaccinations. However, response rates to non-
live vaccines may be reduced. In a randomized study, patients with RA treated with MabThera 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 MabThera as compared to patients
only receiving methotrexate. Should non-live vaccinations be required whilst receiving MabThera
therapy, these should be completed at least 4 weeks prior to commencing the next course of
MabThera.
In the overall experience of MabThera repeat treatment over one year, the proportions of patients with
positive antibody titers against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid
were generally similar to the proportions at baseline.
Concomitant/sequential use of other DMARDs
The concomitant use of MabThera and antirheumatic 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 MabThera (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 MabThera, however patients should be closely observed
for signs of infection if biologic agents and/or DMARDs are used following MabThera therapy.
Malignancy
Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience
with MabThera 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.
Currently, there are limited data on possible drug interactions with MabThera.
9
In CLL patients, co-administration with MabThera 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 MabThera in
rheumatoid arthritis patients.
Patients with human anti-mouse antibody or human anti-chimeric antibody (HAMA/HACA) titres
may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic
monoclonal antibodies.
In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic
DMARD following MabThera. In these patients the rate of clinically relevant infection while on
MabThera was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment
with the biologic DMARD.
Pregnancy
IgG immunoglobulins are known to cross the placental barrier.
B cell levels in human neonates following maternal exposure to MabThera 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. For these reasons MabThera should not be
administered to pregnant women unless the possible benefit outweighs the potential risk.
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing
potential should use effective contraceptive methods during treatment and for 12 months following
MabThera therapy.
Developmental toxicity studies performed in cynomolgus monkeys revealed no evidence of
embryotoxicity in utero. New born offspring of maternal animals exposed to MabThera were noted to
have depleted B cell populations during the post natal phase.
Lactation
Whether rituximab is excreted in human milk is not known. However, because maternal IgG is
excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should
not breastfeed while treated with MabThera and for 12 months following MabThera treatment.
No studies on the effects of MabThera on the ability to drive and use machines have been performed,
although the pharmacological activity and adverse events reported to date do not indicate that such an
effect is likely.
Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia
The overall safety profile of MabThera in non-Hodgkin’s lymphoma and chronic lymphocytic
leukaemia is based on data from patients from clinical trials and from post-marketing surveillance.
These patients were treated either with MabThera 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 MabThera were
infusion-related reactions which occurred in the majority of patients during the first infusion. The
10
incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less
than 1 % after eight doses of MabThera.
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 trial in patients
with CLL.
The most frequent reported or observed
serious
adverse drug reactions were:
•
Infusion-related reactions (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.).
The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are
summarised in the tables below. 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) and uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1000). The
ADRs identified only during post-marketing surveillance, and for which a frequency could not be
estimated, are listed under “unknown”.
Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients
with NHL and CLL disease treated with MabThera monotherapy/maintenance or in
combination with chemotherapy
System Organ
Class
Very Common
Common
Uncommon
Unknown
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 B
1
serious viral
infection
2
,
Blood and
lymphatic
system disorders
neutropenia,
leucopenia,
+
febrile
neutropenia,
+
thrombocytopenia
anaemia,
+
pancytopenia,
+
granulocytopenia
coagulation
disorders,
aplastic anaemia,
haemolytic
anaemia,
lymphadenopathy
late neutropenia
3
,
transient increase
in serum IgM
levels
3
Immune system
disorders
infusion related
reactions,
angioedema
hypersensitivity
tumour lysis
syndrome
4
,
cytokine release
syndrome
4
, serum
sickness,
anaphylaxis,
infusion-related
acute reversible
thrombocytopenia
4
11
System Organ
Class
Very Common
Common
Uncommon
Unknown
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
cranial
neuropathy,
peripheral
neuropathy
facial nerve
palsy
5
,
loss of other
senses
5
Eye disorders
lacrimation
disorder,
conjunctivitis
severe vision loss
5
Ear and
labyrinth
disorders
tinnitus, ear pain
hearing loss
5
Cardiac
disorders
+
myocardial
infarction
4 and 6
,
arrhythmia,
+
atrial
fibrillation,
tachycardia,
+
cardiac disorder
+
left ventricular
failure,
+
supraventricular
tachycardia,
+
ventricular
tachycardia,
+
angina,
+
myocardial
ischaemia,
bradycardia,
heart failure
4 and 6
,
severe cardiac
events
4 and 6
Vascular
disorders
hypertension,
orthostatic
hypotension,
hypotension
vasculitis
(predominately
cutaneous),
leukocytoclastic
vasculitis
Respiratory,
thoracic and
mediastinal
disorders
Bronchospasm
4
,
respiratory
disease, chest
pain, dyspnoea,
increased cough,
rhinitis
asthma,
bronchiolitis
obliterans, lung
disorder, hypoxia
respiratory
failure
4
,
pulmonary
infiltrates,
interstitial lung
disease
7
Gastrointestinal
disorders
nausea
vomiting
,
diarrhoea,
abdominal pain,
dysphagia,
stomatitis,
constipation,
dyspepsia,
anorexia, throat
irritation
abdominal
enlargement
gastro-intestinal
perforation
7
12
System Organ
Class
Very Common
Common
Uncommon
Unknown
Skin and
subcutaneous
tissue disorders
pruritis, rash,
+
urticaria,
sweating, night
sweats,
+
skin
disorder
severe bullous
skin reactions,
toxic epidermal
necrolysis
7
Musculoskeletal,
connective tissue
and bone
disorders
hypertonia,
myalgia,
arthralgia, back
pain, neck pain,
pain
Renal and
urinary
disorders
renal failure
4
General
disorders and
administration
site conditions
fever
, chills,
asthenia, headache
tumour pain,
flushing, malaise,
cold syndrome,
+
fatigue,
+
pain at the
infusion site
shivering,
multi-organ
failure
4
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 MabThera
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 MabThera-arms compared to control arms:
haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.
Infusion-related reactions
Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of
patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one
to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included
flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat
irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia,
asthenia and features of tumor 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 events (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 MabThera(-containing) treatment.
Infections
MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreased
serum immunoglobulins only in a minority of patients.
13
alopecia
+
Localized candida infections as well as Herpes zoster was reported at a higher incidence in the
MabThera-containing arm of randomized studies. Severe infections were reported in about 4% of
patients treated with MabThera monotherapy. Higher frequencies of infections overall, including
grade 3 or 4 infections, were observed during MabThera 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 MabThera treatment. The majority of patients had
received MabThera in combination with chemotherapy or as part of a hematopoetic stem cell
transplant. Examples of these serious viral infections are infections caused by the herpes viruses
(Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal
leukoencephalopathy (PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease
progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation,
have been reported, the majority of which were in subjects receiving MabThera 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 MabThera 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
MabThera 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. In studies with MabThera 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 MabThera and chemotherapy was not associated with a higher incidence of
infections and infestations compared to patients treated with chemotherapy alone and the neutropenia
was not prolonged in the MabThera plus chemotherapy group. 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 MabThera 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 MabThera 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 reactions
Cardiovascular reactions during clinical trials with MabThera 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 MabThera and observation. Cardiac events were
reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular
failure, myocardial ischemia) in 3% of patients treated with MabThera compared to <1% on
observation. In studies evaluating MabThera 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 MabThera
14
infusion or were associated with predisposing conditions such as fever, infection, acute myocardial
infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP
and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart
failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall
incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and
in the relapsed/refractory study (4% R-FC, 4% FC).
Respiratory system
Cases of interstitial lung disease, some with fatal outcome have been reported.
Neurologic events
During the treatment period, four patients (2 %) treated with R-CHOP, all with cardiovascular risk
factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There
was no difference between the treatment groups in the incidence of other thromboembolic events. In
contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred
during the follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders
was low both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC,
3% FC).
Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior
leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual
disturbance, headache, seizures and altered mental status, with or without associated hypertension. A
diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognized
risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension,
immunosuppressive therapy and/or chemotherapy.
Gastrointestinal disorders
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving
MabThera for treatment of non Hodkgin lymphoma. In the majority of these cases, MabThera was
administered with chemotherapy.
IgG levels
In the clinical trial evaluating MabThera 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 MabThera groups. In the observation group, the median IgG
level subsequently increased to above the LLN, but remained constant in the MabThera group. The
proportion of patients with IgG levels below the LLN was about 60% in the MabThera group
throughout the 2 year treatment period, while it decreased in the observation group (36% after
2 years).
Patient subpopulations - MabThera monotherapy
Elderly patients (≥ 65 years):
The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared to
younger patients (<65 years).
Bulky disease
There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients
without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in these
two groups.
Re-treatment
The percentage of patients reporting ADRs upon re-treatment with further courses of MabThera was
similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4
ADRs).
Patient subpopulations - MabThera combination therapy
15
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
The overall safety profile of MabThera in rheumatoid arthritis is based on data from patients from
clinical trials and from post-marketing surveillance.
The safety profile of MabThera in patients with severe rheumatoid arthritis (RA) is summarized 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 MabThera (see section 4.4).
Patients received 2 x 1000 mg of MabThera separated by an interval of two weeks; in addition to
methotrexate (10-25 mg/week). MabThera infusions were administered after an intravenous infusion
of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days.
Events are listed in Table 2. Frequencies are defined as very common (≥1/10), common (≥1/100 to
<1/10), uncommon (≥1/1,000 to <1/100), and very rare (<1/10,000). Within each frequency grouping,
undesirable effects are presented in order of decreasing seriousness.
The most frequent adverse reaction considered due to receipt of MabThera were infusion related
reactions. 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
postmarketing surveillance occurring in patients with rheumatoid arthritis receiving
MabThera
System Organ
Class
Very Common
Common
Uncommon
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
Serum sickness-
like reaction
Immune System
Disorders
General
disorders and
administration
site conditions
*Infusion related
reactions
(hypertension,
nausea, rash,
pyrexia, pruritis,
urticaria, throat
irritation, hot flush,
hypotension,
rhinitis, rigors,
tachycardia,
fatigue,
oropharyngeal pain,
peripheral oedema,
erythema)
*Infusion
related
reactions
(generalized
oedema,
bronchospasm,
wheezing,
laryngeal
oedema,
angioneurotic
oedema,
generalized
pruritis,
anaphylaxis,
anaphylactoid
16
System Organ
Class
Very Common
Common
Uncommon
Very rare
reaction)
Metabolism and
Nutritional
Disorders
hypercholesterolemia
Nervous System
disorders
headache
paraesthesia,
migraine, dizziness,
sciatica
Skin and
Subcutaneous
Tissue Disorders
alopecia
Psychiatric
Disorders
depression, anxiety
Gastrointestinal
Disorders
Dyspepsia,
diarrhoea, gastro-
oesophageal reflux,
mouth ulceration,
upper abdominal
pain
Musculo skeletal
disorders
arthralgia /
musculoskeletal pain,
osteoarthritis ,
bursitis
*Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. Infusion related
reactions may occur as a result of hypersensitivity and/or to the mechanism of action.
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 MabThera exposure was highest during the first 6
months and declined thereafter. This is mostly accounted for by infusion-related reactions (most
frequent during the first treatment course), RA exacerbation and infections, all of which were more
frequent in the first 6 months of treatment.
Infusion-related reactions
The most frequent ADRs following receipt of MabThera in clinical studies were infusion-related
reactions (IRRs) (refer to Table 2). Among the 3189 patients treated with MabThera, 1135 (36%)
experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first
infusion of the first exposure to MabThera. The incidence of IRRs decline for all subsequent infusions.
In clinical studies fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC
Grade 4 IRRs and no deaths due to IRRs. 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 section 4.2).
Infections
The overall rate of infection was approximately 94 per 100 patient years in MabThera 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
antibiotic was approximately 4 per 100 patient years. The rate of serious infections did not show any
significant increase following multiple courses of MabThera. Lower respiratory tract infections
(including pneumonia) have been reported during clinical trials, at a similar incidence in the Mabthera
arms compared to control arms.
Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported following
use of MabThera for the treatment of autoimmune diseases. This includes Rheumatoid Arthritis and
off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and Vasculitis.
17
In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic
chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma).
Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving
MabThera (see Section 4.4).
Cardiovascular
Serious cardiac events were reported at a rate of 1.3 per 100 patient years in the MabThera treated
patients compared to 1.3 per 100 patients years in placebo treated patients. The proportions of patients
experiencing cardiac events (all or serious) did not increase over multiple courses.
There has been no experience of overdose in human clinical trials. However, single doses higher than
1000 mg have not been tested in controlled clinical trials. in patients with autoimmune disease. The
highest dose tested to date is 5g in patients with chronic lymphocytic leukaemia. No additional safety
signals were identified.
In the postmarketing 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: monoclonal antibodies
,
ATC code: L01X C02
Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated
phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95 % of all
B cell non-Hodgkin’s lymphomas.
CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro-
B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon antibody
binding and is not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen
and, thus, does not compete for antibody binding.
The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can
recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated
cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and
antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the
surface of granulocytes, macrophages and NK cells. Rituximab binding to CD 20 antigen on B
lymphocytes has also been demonstrated to induce cell death via apoptosis.
Peripheral B cell counts declined below normal following completion of the first dose of MabThera. In
patients treated for hematological malignancies, B cell repletion began within 6 months of treatment
returning to normal levels between 9 and 12 months after completion of therapy. In rheumatoid
arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two
infusions of 1000 mg MabThera 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 MabThera was administered as monotherapy or in combination with methotrexate.
Clinical Experience in Non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia
Follicular lymphoma
18
Monotherapy
Initial treatment, weekly for 4 doses
In the pivotal study, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL
received 375 mg/m
2
of MabThera as an intravenous infusion once weekly for four weeks. The overall
response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI
95
% 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 MabThera. A statistically significant correlation was noted between response rates and
bone marrow involvement. 40 % of patients with bone marrow involvement responded compared to
59 % of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a
stepwise logistic regression analysis in which the following factors were identified as prognostic
factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky
disease.
Initial treatment, weekly for 8 doses
In a multi-centre, single-arm study, 37 patients with relapsed or chemoresistant, low grade or follicular
B cell NHL received 375 mg/m
2
of MabThera 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 studies, 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 MabThera as
intravenous infusion weekly for four doses. The ORR was 36 % (CI
95
% 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 study, 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 MabThera, were re-
treated with 375 mg/m
2
of MabThera as intravenous infusion weekly for four doses. Three of the
patients had received two courses of MabThera before enrollment 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 % (CI
95
% 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 MabThera (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/m
2
,
vincristine 1.4 mg/m
2
up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m
2
/day on days
1 -5) every 3 weeks for 8 cycles or MabThera 375 mg/m
2
in combination with CVP (R-CVP).
MabThera 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).
19
The difference between the treatment groups with respect to overall survival showed a significant
clinical difference (p=0.029, log-rank test stratified by center): 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 randomized trials using MabThera 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 summarized in table 3.
Table 3
Summary of key results from four phase III randomized studies evaluating the
benefit of MabThera with different chemotherapy regimens in follicular lymphoma
Study
Treatment,
N
Median
FU,
months
ORR, %
CR,
%
Median
TTF/PFS/ EFS
mo
OS
rates,
%
M39021
CVP, 159
R-CVP, 162
53
57
81
10
41
Median TTP:
14.7
33.6
P<0.0001
53-months
71.1
80.9
p=0.029
GLSG’00
CHOP, 205
R-CHOP,
223
18
90
96
17
20
Median TTF: 2.6
years
Not reached
p < 0.001
18-months
90
95
p = 0.016
OSHO-39
MCP, 96
R-MCP, 105
47
75
92
25
50
Median PFS: 28.8
Not reached
p < 0.0001
48-months
74
87
p = 0.0096
FL2000
CHVP-IFN,
183
R-CHVP-
IFN, 175
42
85
94
49
76
Median EFS: 36
Not reached
p < 0.0001
42-months
84
91
p = 0.029
EFS – Event Free Survival
TTP – Time to progression or death
PFS – Progression-Free Survival
TTF – Time to Treatment Failure
OS rates – survival rates at the time of the analyses
Maintenance therapy
Previously untreated follicular lymphoma
In a prospective, open label, international, multi-center, 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 randomized to MabThera maintenance therapy (n=505) or
observation (n=513). The two treatment groups were well balanced with regards to baseline
characteristics and disease status. MabThera maintenance treatment consisted of a single infusion of
MabThera at 375 mg/m2 body surface area given every 2 months until disease progression or for a
maximum period of two years.
20
After a median observation time of 25 months from randomization, maintenance therapy with
MabThera resulted in a clinically relevant and statistically significant improvement in the primary
endpoint of investigator assessed progression-free survival (PFS) as compared to oberservation in
patients with previously untreated follicular lymphoma (Table 4).
Significant benefit from maintenance treatment with MabThera 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) (Table 4).
Table 4
Maintenance phase: overview of efficacy results MabThera vs. observation (25
months median observation time)
Observation
N=513
Rituximab
N=505
Log-rank P
value
Risk reduction
Primary Efficacy
PFS (median)
NR
NR
<0.0001
50%
Secondary Efficacy
EFS (median)
37.8 months
NR
< 0.0001
46%
OS (median)
NR
NR
0.7246
11%
TNLT (median)
NR
NR
0.0003
39%
TNCT (median)
NR
NR
0.0011
40%
ORR*
55.0%
74.0%
< 0.0001
[Odds ratio =
2.33]
Complete Response
(CR/CRu) rate*
47.7%
66.8%
< 0.0001
[Odds ratio =
2.21]
*At end of maintenance/observation;
PFS: progression-free survival; EFS: event-free survival; OS: overall survival; TNLT: time to next anti-lymphoma treatment;
TNCT: Time to next chemotherapy treatment; ORR: overall response rate: NR: Not Reached at time of clinical cut-off
MabThera 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 MabThera 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 MabThera maintenance therapy
(n=167) or observation (n=167). MabThera maintenance treatment consisted of a single infusion of
MabThera at 375 mg/m
2
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 randomized 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 5).
Table 5
Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months
median observation time)
CHOP
R-CHOP
p-value
Risk Reduction
1)
Primary Efficacy
21
CHOP
R-CHOP
p-value
Risk Reduction
1)
ORR
2)
74 %
87 %
0.0003
Na
CR
2)
16 %
29 %
0.0005
Na
PR
2)
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 randomized to the maintenance phase of the trial, the median observation time was 28
months from maintenance randomisation. Maintenance treatment with MabThera 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 MabThera 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 MabThera maintenance
treatment when compared to observation (95 % CI; 45 %-72 %). Kaplan-Meier estimated progression-
free rates at 12 months were 78 % in the MabThera maintenance group vs. 57 % in the observation
group. An analysis of overall survival confirmed the significant benefit of MabThera maintenance
over observation (p=0.0039 log-rank test). MabThera maintenance treatment reduced the risk of death
by 56 % (95 % CI; 22 %-75 %).
Table 6
Maintenance phase: overview of efficacy results MabThera vs. observation (28
months median observation time)
Kaplan-Meier Estimate of
Median Time to Event (Months)
Efficacy Parameter
Risk
Reduction
Observation
(N = 167)
MabThera
(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 survival
a
16.5
53.7
0.0003
67 %
Subgroup Analysis
11.6
22.1
14.3
14.3
37.5
51.9
52.8
37.8
< 0.0001
0.0071
0.0008
< 0.0001
71 %
46 %
64 %
54 %
CHOP
R-CHOP
CR
PR
OS
NR
NR
NR
NR
0.0348
0.0482
55 %
56 %
CHOP
R-CHOP
NR: not reached;
a
: only applicable to patients achieving a CR
The benefit of MabThera 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 6). MabThera 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, MabThera maintenance treatment provided a significant benefit in terms of
22
PFS
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/m
2
, doxorubicin 50 mg/m
2
, vincristine 1.4 mg/m
2
up to a maximum of 2 mg on day 1, and
prednisolone 40 mg/m
2
/day on days 1-5) every 3 weeks for eight cycles, or MabThera 375 mg/m
2
plus
CHOP (R-CHOP). MabThera was administered on the first day of the treatment cycle.
The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a
median follow-up duration of approximately 31 months. The two treatment groups were well balanced
in baseline disease characteristics and disease status. The final analysis confirmed that R-CHOP
treatment was associated with a clinically relevant and statistically significant improvement in the
duration of event-free survival (the primary efficacy parameter; where events were death, relapse or
progression of lymphoma, or institution of a new anti-lymphoma treatment) (p = 0.0001). Kaplan
Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm
compared to 13 months in the CHOP arm, representing a risk reduction of 41 %. At 24 months,
estimates for overall survival were 68.2 % in the R-CHOP arm compared to 57.4 % in the CHOP arm.
A subsequent analysis of the duration of overall survival, carried out with a median follow-up duration
of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), representing a risk
reduction of 32 %.
The analysis of all secondary parameters (response rates, progression-free survival, disease-free
survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The
complete response rate after cycle 8 was 76.2 % in the R-CHOP group and 62.4 % in the CHOP group
(p=0.0028). The risk of disease progression was reduced by 46 % and the risk of relapse by 51 %.
In all patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2 microglobulin,
LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow involvement), the risk
ratios for event-free survival and overall survival (R-CHOP compared with CHOP) were less than
0.83 and 0.95 respectively. R-CHOP was associated with improvements in outcome for both high- and
low-risk patients according to age adjusted IPI.
Clinical laboratory findings
Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of
356 patients evaluated for HACA, 1.1 % (4 patients) were positive.
Chronic lymphocytic leukaemia
In two open-label randomized trials, a total of 817 previously untreated patients and 552 patients with
relapsed/refractory CLL were randomized to receive either FC chemotherapy (fludarabine 25 mg/m
2
,
cyclophosphamide 250 mg/m
2
, days 1-3) every 4 weeks for 6 cycles or MabThera in combination with
FC (R-FC). MabThera was administered at a dosage of 375 mg/m
2
during the first cycle one day prior
to chemotherapy and at a dosage of 500 mg/m
2
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 7a and Table 7b) and 552 patients (276 R-FC, 276 FC) for the
relapsed/refractory study (Table 8) were analyzed for efficacy.
In the first-line study, the median progression-free survival (primary endpoint) was 40 months in the
R-FC group and 32 months in the FC group (p < 0.0001, log-rank test). The analysis of overall
survival showed an improved survival in favour of the R-FC arm (p=0.0427, log-rank test), however
longer follow-up is needed to confirm this observation.
The benefit in terms of PFS was consistently
observed in most patient subgroups analyzed according to disease risk at baseline.
Table 7a First-line treatment of chronic lymphocytic leukaemia
23
Overview of efficacy results for MabThera plus FC vs. FC alone (20.7 months
median observation time)
Efficacy Parameter
Kaplan-Meier Estimate of
Median Time to Event (Months)
Risk
Reduction
FC
(N = 407)
R-FC
(N=403)
Log-Rank
p value
Progression-free survival (PFS)
32.2
39.8
<0.0001
44%
Overall Survival
NR
NR
0.0427
36%
Event Free Survival
31.1
39.8
<0.0001
45%
Response rate (CR, nPR, or PR)
72.7%
86.1%
<0.0001
n.a.
CR rates
17.2%
36.0%
<0.0001
n.a.
Duration of response*
34.7
40.2
0.0040
39%
Disease free survival (DFS)**
NR.
NR
0.7882
7%
Time to new treatment
NR.
NR
0.0052
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;
Table 7b First-line treatment of chronic lymphocytic leukaemia
Progression-Free Survival according to Binet stage (ITT)
Number of
patients
Hazard Ratio
(95% CI)
p-value (Wald
test, not
adjusted)
FC
R-FC
Binet A
22
18
0.13 (0.03; 0.61)
0.0093
Binet B
257
259
0.45 (0.32; 0.63)
<0.0001
Binet C
126
125
0.88 (0.58; 1.33)
0.5406
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 analyzed 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.
24
Progression-free survival (PFS)
Table 8
Treatment of relapsed/refractory chronic lymphocytic leukaemia - overview of
efficacy results for MabThera 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)
58.0%
69.9%
0.0034
n.a.
CR rates
13.0%
24.3%
0.0007
n.a.
Duration of response
*
27.6
39.6
0.0252
31%
Disease free survival (DFS)**
42.2
39.6
0.8842
-6%
Time to new CLL treatment
34.2
NR
0.0024
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 MabThera 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 MabThera with any chemotherapy.
Data in approximately 180 patients pre-treated with MabThera have demonstrated clinical benefit
(including CR) and are supportive for MabThera re-treatment.
Clinical Experience in rheumatoid arthritis
The efficacy and safety of MabThera in alleviating the symptoms and signs of rheumatoid arthritis in
patients with an inadequate response to TNF-inhibitiors was demonstrated in a pivotal randomized,
controlled, double-blind, multicenter study (Study 1).
Study 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). MabThera was administered as two IV
infusions separated by an interval of 15 days. Patients received 2 x 1000 mg intravenous infusions of
MabThera 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.
Studies 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. MabThera 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.
25
Disease activity outcomes
MabThera 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 9). 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 9
Clinical response outcomes at primary endpoint in study 1(ITT popula
tion)
Outcome†
Placebo+MTX
Rituximab+MTX
(2 x 1000 mg)
Study 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 MabThera in combination with methotrexate had a significantly greater
reduction in disease activity score (DAS28) than patients treated with methotrexate alone (Table 9).
Similarly, a good to moderate European League Against Rheumatism (EULAR) response was
achieved by significantly more MabThera treated patients treated with MabThera and methotrexate
compared to patients treated with methotrexate alone (Table 9).
Radiographic response
Structural joint damage was assessed radiographically and expressed as change in modified Total
Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.
In Study 1, conducted in patients with inadequate response or intolerance to one or more TNF
inhibitor therapies, receiving MabThera 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 MabThera/MTX treatment also had no erosive progression over 56 weeks (Table 10).
26
Table 10 Radiographic outcomes at 1 year (mITT population)
Placebo+MTX
Rituximab +MTX
2 × 1000 mg
Study 1
(n = 184)
(n = 273)
Mean Change from Baseline:
Modified Total Sharp score
2.31
1.00
*
Erosion Score
1.32
0.59
*
Joint Space narrowing score
0.99
0.41
**
Proportion of patients with no radiographic
change
46%
53%
Proportion of patients with no erosivechange 52% 61%
*
150 patients originally randomized to placebo + MTX in Study 1 received at least one course of RTX + MTX by one year
* p <0 05, ** p < 0.001,
Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis
at 2 years in study 1 demonstrated significantly reduced progression of structural joint damage in
patients receiving MabThera 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 MabThera 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 11).
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 11).
Table 11 Physical Function and Quality of Life outcomes at week 24 in study 1
Outcome†
Placebo+MTX Rituximab+MTX
(2 x 1000 mg)
Mean change in HAQ-DI
n=201
0.1
n=298
-0.4
***
% HAQ-DI MCID
20%
51%
Mean change in FACIT-T
-0.5
-9.1
***
n=197
0.9
n=294
5.8
***
Mean Change in SF-36 PHS
% 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
27
Patients seropositive to Rheumatoid Factor (RF) and/or anti- Cyclic Citrullinated Peptide (anti-CCP)
who were treated with MabThera in combination with methotrexate showed an enhanced response
compared to patients negative to both.
Efficacy outcomes in MabThera 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 12). 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 12 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 MabThera 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.
28
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)
90
80
70
60
ACR20
ACR50
ACR70
50
40
30
20
10
0
1st
Course
2nd
Course
3rd
Course
4th
Course
Clinical laboratory finding
A total of 392/3095 (12.7%) patients with rheumatoid arthritis tested positive for HACA in clinical
studies following therapy with MabThera. The emergence of HACA was not associated with clinical
deterioration or with an increased risk of reactions to subsequent infusions in the majority of patients.
The presence of HACA may be associated with worsening of infusion or allergic reactions after the
second infusion of subsequent courses.
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/m
2
), the typical population estimates of nonspecific clearance (CL
1
),
specific clearance (CL
2
) likely contributed by B cells or tumor burden, and central compartment
volume of distribution (V
1
) 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 tumor lesions contributed to some of the variability in CL
2
of rituximab in data from 161 patients given 375 mg/m
2
as an intravenous infusion for 4 weekly doses.
Patients with higher CD19-positive cell counts or tumor lesions had a higher CL
2
. However, a large
component of inter-individual variability remained for CL
2
after correction for CD19-positive cell
counts and tumor lesion size. V
1
varied by body surface area (BSA) and CHOP therapy. This
variability in V
1
(27.1% and 19.0%) contributed by the range in BSA (1.53 to 2.32 m
2
) 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/m
2
at weekly intervals for 4
doses to 203 patients with NHL naive to rituximab, yielded a mean C
max
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/m
2
as an intravenous infusion at weekly
intervals for 8 doses to 37 patients with NHL, the mean C
max
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/m
2
in
combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.
29
Chronic lymphocytic leukaemia
Rituximab was administered as an IV infusion at a first-cycle dose of 375 mg/m
2
increased to
500 mg/m
2
each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL
patients. The mean C
max
(N=15) was 408 µg/ml (range, 97 – 764 µg/ml) after the fifth 500 mg/ m
2
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 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 C
max
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 C
max
ranged from 183 to 198 μg/ml for the 2 × 500 mg dose
and ranged from 355 to 404 μg/ml for the 2 × 1000 mg dose. Mean terminal elimination half-life
ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days for the 2 × 1000 mg dose
group. Mean C
max
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 C
max
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. C
max
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.
5.3 Preclinical safety data
Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in
cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of
B cells in peripheral blood and in lymphoid tissue.
Developmental toxicity studies have been performed in cynomolgus monkeys at dosages up to
100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus
due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid
organs of the foetuses was observed, which persisted post natally and was accompanied by a decrease
in IgG level in the newborn animals affected. B cell counts returned to normal in these animals within
6 months of birth and did not compromise the reaction to immunization.
30
No long-term animal studies have been performed to establish the carcinogenic potential of rituximab,
or to determine its effects on fertility in males or females. Standard tests to investigate mutagenicity
have not been carried out, since such tests are not relevant for this molecule. However, due to its
character it is unlikely that rituximab has any mutagenic potential.
6.
6.1 List of excipients
Sodium citrate
Polysorbate 80
Sodium chloride
Sodium hydroxide
Hydrochloric acid
Water for injections
6.2 Incompatibilities
No incompatibilities between MabThera and polyvinyl chloride or polyethylene bags or infusion sets
have been observed.
6.3 Shelf life
30 months
The prepared infusion solution of MabThera is physically and chemically stable for 24 hours at
2 °C - 8 °C and subsequently 12 hours at room temperature.
From a microbiological point of view, the prepared infusion solution should be used immediately. If
not used immediately, in-use storage times and conditions prior to use are the responsibility of the user
and would normally not be longer than 24 hours at 2 °C – 8 °C, unless dilution has taken place in
controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from
light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10 ml. Packs of 2
vials.
6.6 Special precautions for disposal
MabThera is provided in sterile, preservative-free, non-pyrogenic, single use vials.
Aseptically withdraw the necessary amount of MabThera, 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 discoloration prior to administration.
31
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
EU/1/98/067/001
9.
Date of first authorisation: 2 June 1998
Date of latest renewal: 2 June 2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMA) http://www.ema.europa.eu/
32
1.
MabThera 100 mg concentrate for solution for infusion
Rituximab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 vial contains 10 mg/ml rituximab.
3.
LIST OF EXCIPIENTS
Sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for
injections.
4.
Concentrate for solution for infusion
100 mg / 10 ml
2 vials of 10 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after dilution
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator. Keep the container in the outer carton, in order to protect from light
69
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1/98/067/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
70
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
FURTHER INFORMATION
What MabThera contains
-
The active ingredient in MabThera is called rituximab. The vial contains 500 mg of Rituximab
(10 mg/ml).
-
The other ingredients are sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide,
hydrochloric acid and water for injections.
What MabThera looks like and contents of the pack
MabThera is a clear, colourless solution, supplied as a concentrate for solution for infusion. Pack of 1
vial.
Marketing Authorisation Holder
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
Manufacturer
Roche Pharma AG
Emil-Barell-Str. 1
D-79639 Grenzach-Wyhlen
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
89
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Roche Farma S.A.
Tel: +34 - 91 324 81 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
France
Roche
Tél: +33 (0) 1 46 40 50 00
România
Roche România S.R.L.
Tel: +40 21 206 47 01
Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700
Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00
Ísland
Roche a/s
c/o Icepharma hf
Sími: +354 540 8000
Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201
Italia
Roche S.p.A.
Tel: +39 - 039 2471
Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500
Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76
Sverige
Roche AB
Tel: +46 (0) 8 726 1200
Latvija
Roche Latvija SIA
Tel: +371 – 6 7 039831
United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
This leaflet was last approved in
90
Source: European Medicines Agency
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