MABTHERA 1400mg 120mg / ml injectible solution medication leaflet

MabThera 1400 mg solution for subcutaneous injection

Each mL contains 120 mg of rituximab.

Each vial contains 1400 mg/11.7 mL rituximab.

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

For the full list of excipients, see section 6.1.

Solution for injection.

Clear to opalescent, colourless to yellowish liquid with pH of 5.2 - 5.8 and osmolality of300 - 400 mOsmol/kg.

MabThera is indicated in adults for non-Hodgkin’s lymphoma (NHL):

MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicularlymphoma in combination with chemotherapy.

MabThera maintenance therapy is indicated for the treatment of follicular lymphoma patientsresponding to induction therapy.

MabThera is indicated for the treatment of patients with CD20 positive diffuse large B-cellnon-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine,prednisolone) chemotherapy.

MabThera should be administered under the close supervision of an experienced healthcareprofessional, and in an environment where full resuscitation facilities are immediately available (seesection 4.4).

Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol anddiphenhydramine, should always be given before each administration of MabThera.

Premedication with glucocorticoids should be considered if MabThera is not given in combinationwith glucocorticoid-containing chemotherapy.

The recommended dose of MabThera subcutaneous formulation used for adult patients is asubcutaneous injection at a fixed dose of 1400 mg irrespective of the patient’s body surface area.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a fulldose of MabThera by intravenous infusion, using MabThera intravenous formulation (see section 4.4).

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch,they should continue the subsequent cycles with MabThera intravenous formulation until a fullintravenous dose is successfully administered.

Therefore, the switch to MabThera subcutaneous formulation can only occur at the second orsubsequent cycles of treatment.

It is important to check the medicinal product labels to ensure that the appropriate formulation(intravenous or subcutaneous formulation) and strength is being given to the patient, as prescribed.

MabThera subcutaneous formulation is not intended for intravenous administration and should be givenvia subcutaneous injection only. The 1400 mg strength is intended for subcutaneous use innon-Hodgkin’s lymphoma (NHL) only.

The recommended dose of MabThera in combination with chemotherapy for induction treatment ofpreviously untreated or relapsed/refractory patients with follicular lymphoma is: first cycle with

MabThera intravenous formulation 375 mg/m2 body surface area, followed by subsequent cycles with

MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle for up to 8 cycles.

MabThera should be administered on Day 1 of each chemotherapy cycle, after administration of theglucocorticoid component of the chemotherapy if applicable.

* Previously untreated follicular lymphoma

The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment forpatients with previously untreated follicular lymphoma who have responded to induction treatment is:1400 mg once every 2 months (starting 2 months after the last dose of induction therapy) until diseaseprogression or for a maximum period of two years (12 administrations in total).

* Relapsed/refractory follicular lymphoma

The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment forpatients with relapsed/refractory follicular lymphoma who have responded to induction treatment is:1400 mg once every 3 months (starting 3 months after the last dose of induction therapy) until diseaseprogression or for a maximum period of two years (8 administrations in total).

Diffuse large B-cell non-Hodgkin's lymphoma

MabThera should be used in combination with CHOP chemotherapy. The recommended dose is: firstcycle, MabThera intravenous formulation: 375 mg/m2 body surface area, followed by subsequent cycleswith MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle. In total:8 cycles.

MabThera is administered on Day 1 of each chemotherapy cycle after intravenous infusion of theglucocorticoid component of CHOP.

Safety and efficacy of MabThera have not been established in combination with other chemotherapies i ndiffuse large B-cell non-Hodgkin’s lymphoma.

No dose reductions of MabThera are recommended. When MabThera is given in combination withchemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied(see section 4.8).

The safety and efficacy of MabThera in children aged below 18 years has not been established. No dataare available.

No dose adjustment is required in patients aged 65 years and above.

Subcutaneous injections:

MabThera 1400 mg subcutaneous formulation should be administered as subcutaneous injection only,over approximately 5 minutes. The hypodermic injection needle must only be attached to the syringeimmediately prior to administration to avoid potential needle clogging.

MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall andnever into areas where the skin is red, bruised, tender, hard or areas where there are moles or scars.

No data are available on performing the injection in other sites of the body, therefore injections shouldbe restricted to the abdominal wall.

During the treatment course with MabThera subcutaneous formulation, other medicinal products forsubcutaneous administration should preferably be given at different sites.

If an injection is interrupted it can be resumed at the same site or another location may be used, ifappropriate.

Hypersensitivity to the active substance or to murine proteins, hyaluronidase or to any of the excipientslisted in section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

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

The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation i nthe approved indications Treatment of non-Hodgkin’s lymphoma (strength 1400 mg) and Treatment ofchronic lymphocytic leukaemia (strength 1600 mg). For information related to the other indications,please refer to the SmPC of MabThera intravenous formulation.

The use of MabThera subcutaneous formulation as monotherapy in patients with stage III-IV follicularlymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapycannot be recommended as the safety of the once weekly subcutaneous administration has not beenestablished.

Use of MabThera may be associated with an increased risk of progressive multifocalleukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worseningneurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosingmust be suspended until PML has been excluded. The clinician should evaluate the patient to determineif the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms arepossibly suggestive of PML. Consultation with a neurologist should be considered as clinically indicated.

If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid(CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may notnotice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to informtheir partner or caregivers about their treatment, since they may notice symptoms that the patient is notaware of.

If a patient develops PML, the dosing of MabThera must be permanently discontinued. Followingreconstitution of the immune system in immunocompromised patients with PML, stabilisation orimproved 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.

Infusion/Administration-related reactions

MabThera is associated with infusion/administration-related reactions, which may be related to release ofcytokines and/or other chemical mediators. Cytokine release syndrome may be clinicallyindistinguishable from acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome andanaphylactic and hypersensitivity reactions are described below. They are not specifically related tothe route of administration of MabThera and can be observed with both formulations.

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

Severe cytokine release syndrome is characterised by severe dyspnea, often accompanied bybronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. Thissyndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia,hyperkalaemia, hypocalcaemia, hyperphosphaetemia, acute renal failure, elevated lactatedehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acuterespiratory 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 initiatingthe first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumourinfiltration 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 interruptedimmediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initialimprovement of clinical symptoms may be followed by deterioration, these patients should be closelymonitored 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 inrepeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (≥ 25 x 109/L) of circulating malignant cells,who may be at higher risk of especially severe cytokine release syndrome, should be treated withextreme 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 patientsor a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte countis still > 25 x 109/L.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenousadministration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivityreactions typically occur within minutes after starting infusion. Medicinal products for the treatment ofhypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should beavailable 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 cytokinerelease syndrome (described above). Reactions attributed to hypersensitivity have been reported lessfrequently than those attributed to cytokine release.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonaryoedema and acute reversible thrombocytopenia.

Since hypotension may occur during MabThera administration, consideration should be given towithholding anti-hypertensive medicines 12 hours prior to giving MabThera.

Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated with

MabThera intravenous formulation (including cytokine release syndrome accompanied by hypotensionand bronchospasm in 10% of patients) see section 4.8. These symptoms are usually reversible withinterruption of MabThera infusion and administration of an anti-pyretic, an antihistaminic, and,occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please seecytokine release syndrome above for severe reactions.

Administration related reactions have been observed in up to 50% of patients treated with MabTherasubcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the subcutaneousinjection consisted primarily of erythema pruritus, rash and injections site reactions such as pain,swelling and redness and were generally of mild or moderate (grade 1 or 2) and transient nature (seesection 4.8).

Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinicaltrials. Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (seesection 4.8). Some local cutaneous reactions occurred more than 24 hours after the MabTherasubcutaneous administration. The majority of local cutaneous reactions seen following administration of

MabThera subcutaneous formulation was mild or moderate and resolved without any specific treatment.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a fulldose of MabThera by intravenous infusion, using MabThera intravenous formulation. The highest risk ofexperiencing an administration related reaction is generally observed at cycle one. Beginning the therapywith MabThera intravenous infusion would allow a better handling of the administration reactions byslowing or stopping the intravenous infusion.

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch,they should continue the subsequent cycles with MabThera intravenous formulation until a fullintravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneousformulation can only occur at the second or subsequent cycles of treatment.

As with the intravenous formulation, MabThera subcutaneous formulation should be administered in anenvironment where full resuscitation facilities are immediately available and under the close supervisionof an experienced healthcare professional. Premedication consisting of an analgesic/antipyretic and anantihistamine should always be administered before each dose of MabThera subcutaneous formulation.

Premedication with glucocorticoids should also be considered.

Patients should be observed for at least 15 minutes following MabThera subcutaneous administration. Alonger period may be appropriate in patients with an increased risk of hypersensitivity reactions.

Patients should be instructed to contact their treating physician immediately if symptoms that aresuggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinalproduct administration.

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/ormyocardial infarction have occurred in patients treated with MabThera. Therefore, patients with ahistory of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.

Although MabThera is not myelosuppressive in monotherapy, caution should be exercised whenconsidering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L asclinical experience in this population is limited. The MabThera intravenous formulation has been used in21 patients who underwent autologous bone marrow transplantation and other risk groups with apresumable reduced bone marrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed during

MabThera therapy.

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 ofrecurring or chronic infections or with underlying conditions which may further predispose patients toserious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in patients receiving the MabThera intravenousformulation including fulminant hepatitis with fatal outcome. The majority of these patients were alsoexposed to cytotoxic chemotherapy. Hepatitis B virus (HBV) screening should be performed in allpatients before initiation of treatment with MabThera. At minimum this should include HBsAg-statusand HBcAb-status. These can be complemented with other appropriate markers as per local guidelines.

Patients with active hepatitis B disease should not be treated with MabThera. Patients with positivehepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start oftreatment and should be monitored and managed following local medical standards to prevent hepatitis

B reactivation.

Very rare cases of PML have been reported during post-marketing use of the MabThera intravenousformulation in NHL (see section 4.8). The majority of patients had received rituximab in combinationwith chemotherapy or as part of a haematopoietic stem cell transplant.

Cases of enteroviral meningoencephalitis including fatalities have been reported following use ofrituximab.

False negative serologic testing of infections

Due to the risk of false negative serologic testing of infections, alternative diagnostic tools should beconsidered in case of patients presenting with symptoms indicative of rare infectious disease e.g. West

Nile virus and neuroborreliosis.

The safety of immunisation with live viral vaccines, following MabThera therapy has not been studiedfor NHL 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 bereduced. In a non-randomised study, patients with relapsed low-grade NHL who received the MabTheraintravenous formulation as monotherapy when compared to healthy untreated controls had a lower rateof 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 titre).

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

MabThera.

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

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

Co-administration with MabThera did not appear to have an effect on the pharmacokinetics of fludarabineor cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide onthe pharmacokinetics of MabThera.

Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may haveallergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonalantibodies.

Due to the long retention time of rituximab in B-cell depleted patients, women of childbearing potentialmust employ effective contraceptive methods during and for 12 months after treatment with MabThera.

IgG immunoglobulins are known to cross the placental barrier.

B-cell levels in human neonates following maternal exposure to MabThera have not been studied inclinical trials. There are no adequate and well-controlled data from studies in pregnant women, howevertransient B-cell depletion and lymphocytopenia have been reported in some infants born to mothersexposed to MabThera during pregnancy. Similar effects have been observed in animal studies (seesection 5.3). For these reasons MabThera should not be administered to pregnant women unless thepossible benefit outweighs the potential risk.

Limited data on rituximab excretion into breast milk suggest very low rituximab concentrations in milk(relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normal growthand development up to 2 years. However, as these data are limited and the long-term outcomes ofbreastfed infants remain unknown, breast-feeding is not recommended while being treated with rituximaband optimally for 6 months following rituximab treatment.

Animal studies did not reveal deleterious effects of rituximab or recombinant human hyaluronidase(rHuPH20) on reproductive organs.

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

The information provided in this section pertains to the use of MabThera in oncology.

For information related to the autoimmune indications, please refer to the SmPC of MabTheraintravenous formulation.

During the development programme, the safety profile of MabThera subcutaneous formulation wascomparable to that of the intravenous formulation with the exception of local cutaneous reactions. Localcutaneous reactions, including injection site reactions were very common in patients receiving

MabThera subcutaneous formulation. In the phase 3 SABRINA trial (BO22334), local cutaneousreactions were reported in up to 20% of patients receiving subcutaneous MabThera. The most commonlocal cutaneous reactions in the MabThera subcutaneous arm were injection erythema (13%), injectionpain (7%) and injection site oedema (4%). Events seen following subcutaneous administration were mildor moderate, apart from one patient who reported a local cutaneous reaction of Grade 3 intensity(injection site rash) following the first MabThera subcutaneous administration (Cycle 2). Localcutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the firstsubcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequentinjections.

Adverse reactions reported in MabThera subcutaneous formulation usage

The risk of acute administration-related reactions associated with the subcutaneous formulation of

MabThera was assessed in two open-label trials involving patients with follicular lymphoma duringinduction and maintenance (SABRINA/BO22334) and during maintenance only (SparkThera/BP22333).

In SABRINA, severe administration-related reactions (grade ≥ 3) were reported in two patients (2%)following administration of MabThera subcutaneous formulation. These events were Grade 3 injectionsite rash and dry mouth. In SparkThera, no severe administration-related reactions were reported.

Adverse reactions reported in MabThera intravenous formulation usage

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data frompatients from clinical trials and from post-marketing surveillance. These patients were treated eitherwith MabThera monotherapy (as induction treatment or maintenance treatment following inductiontreatment) or in combination with chemotherapy.

The most frequently observed adverse reactions in patients receiving MabThera were infusion-relatedreactions which occurred in the majority of patients during the first infusion. The incidence ofinfusion-related symptoms decreases substantially with subsequent infusions and is less than 1% aftereight doses of MabThera.

Infectious events (predominantly bacterial and viral) occurred in approximately 30-55% of patients duringclinical 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 reactions were:

* Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.

* Infections, see section 4.4.

* Cardiovascular disorders, see section 4.4.

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

The frequencies of adverse reactions reported with MabThera alone or in combination withchemotherapy are summarised in Table 1. Frequencies are defined as very common (≥ 1/10), common(≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare(< 1/10 000) and not known (cannot be estimated from the available data). Within each frequencygrouping, undesirable effects are presented in order of decreasing seriousness.

The adverse reactions identified only during post-marketing surveillance, and for which a frequencycould not be estimated, are listed under “not known”, see footnotes.

Table 1 Adverse reactions reported in clinical trials or during post-marketing surveillancein patients with NHL and CLL disease treated with MabTheramonotherapy/maintenance or in combination with chemotherapy

MedDRA

System Organ Very

Common Common Uncommon Rare Very Rare Not known

Class

Infections and bacterial sepsis, serious viral enteroviralinfestations infections, +pneumonia, infection2 meningoencephalviral infections, +febrile infection, itis2,3+bronchitis +herpes zoster,+respiratory tractinfection,fungal infections,infections ofunknownaetiology,+acute bronchitis,+sinusitis,hepatitis B1

Blood and neutropenia, anaemia, coagulation transient increase late neutropenia4lymphatic system leucopenia, +pancytopenia, disorders, in serum IgMdisorders +febrile +granulocytopeni aplastic levels4neutropenia, a anaemia,+thrombocytopeni haemolytica anaemia,lymphadenopathy

Immune system Infusion-related hypersensitivity anaphylaxis tumour lysis infusion-relateddisorders reactions5, syndrome, acute reversibleangioedema cytokine release thrombocytopenisyndrome5, a5serum sickness

Metabolism and hyperglycaemia,nutrition weight decrease,disorders oedemaperipheral,face oedema,increased LDH,hypocalcaemia

Psychiatric depression,disorders nervousness,

Nervous system paraesthesia, dysgeusia peripheral cranialdisorders hypoaesthesia, neuropathy, neuropathy,agitation, facial nerve loss of otherinsomnia, palsy6 senses6vasodilatation,dizziness,anxiety

MedDRA

System Organ Very

Common Common Uncommon Rare Very Rare Not known

Class

Eye disorders lacrimation severe visiondisorder, loss6conjunctivitis

Ear and labyrinth tinnitus, hearing loss6disorders ear pain

Cardiac disorders +myocardial +left ventricular severe cardiac heart failure5, 7infarction5, 7, failure, disorders5, 7arrhythmia, +supraventricular+atrial tachycardia,fibrillation, +ventriculartachycardia, tachycardia,+cardiac disorder +angina,+myocardialischaemia,bradycardia

Vascular hypertension, vasculitisdisorders orthostatic (predominatelyhypotension, cutaneous),hypotension leukocytoclasticvasculitis

Respiratory, bronchospasm5, asthma, interstitial lung respiratory lung infiltrationthoracic and respiratory bronchiolitis disease8 failure5mediastinal disease, obliterans,disorders chest pain, lung disorder,dyspnoea, hypoxiaincreased cough,rhinitis

Gastrointestinal nausea vomiting, abdominal gastro-intestinaldisorders diarrhoea, enlargement perforation8abdominal pain,dysphagia,stomatitis,constipation,dyspepsia,anorexia,throat irritation

Skin and pruritis, urticaria, severe bulloussubcutaneous rash, sweating, skin reactions,tissue disorders +alopecia night sweats, Stevens-Johns+skin disorder on Syndrome,toxic epidermalnecrolysis(Lyell’s

Syndrome)8

Musculoskeletal hypertonia,and connective myalgia,tissue disorders arthralgia,back pain,neck pain,pain

Renal and renal failure5urinarydisorders

General fever, tumour pain, infusion sitedisorders and chills, flushing, painadministration asthenia, malaise,site conditions headache coldsyndrome,+fatigue,+shivering,+multi-organfailure5

MedDRA

System Organ Very

Common Common Uncommon Rare Very Rare Not known

Class

Investigations decreased IgGlevels

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 frequencyobserved in the trials is reported1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL2 see also section infection below3 observed during post-marketing surveillance4 see also section haematologic adverse reactions below5 see also section infusion-related reactions below. Rarely fatal cases reported6 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabTheratherapy7 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated withinfusion-related reactions8 includes fatal cases

The following terms have been reported as adverse reactions during clinical trials, however, werereported at a similar or lower incidence in the MabThera-arms compared to control arms:haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% ofpatients in clinical trials involving MabThera intravenous formulation, and were predominantly seenduring the first infusion, usually in the first one to two hours. These symptoms mainly comprisedfever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting,nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia,hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome.

Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of thecases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation,pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiacconditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure,myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysissyndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower orunknown frequencies. The incidence of infusion-related symptoms decreased substantially withsubsequent intravenous infusions and is < 1% of patients by the eighth cycle of MabThera (containing)treatment.

MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreasedserum immunoglobulins only in a minority of patients.

Localised candida infections as well as Herpes zoster were reported at a higher incidence in the

MabThera-containing arm of randomised studies. Severe infections were reported in about 4% ofpatients treated with MabThera monotherapy. Higher frequencies of infections overall, includinggrade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years whencompared to observation. There was no cumulative toxicity in terms of infections reported over a2-year treatment period. In addition, other serious viral infections either new, reactivated orexacerbated, some of which were fatal, have been reported with MabThera treatment. The majority ofpatients had received MabThera in combination with chemotherapy or as part of a haematopoieticstem cell transplant. Examples of these serious viral infections are infections caused by the herpesviruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (PML),enterovirus (meningoencephalitis) and hepatitis C virus (see section 4.4.). Cases of fatal PML thatoccurred after disease progression and retreatment have also been reported in clinical trials. Cases ofhepatitis B reactivation, have been reported, the majority of which were in patients receiving

MabThera in combination with cytotoxic chemotherapy. Progression of Kaposi’s sarcoma has beenobserved in MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred innon-approved indications and the majority of patients were HIV positive.

In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurredin a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia wasreported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During MabTheramaintenance treatment for up to 2 years, leucopoenia (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 ofthrombocytopenia was low (< 1%, grade 3/4) and was not different between treatment arms. During thetreatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopoenia(R-CHOP 88% vs. CHOP 79%), neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP88%), 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 notassociated with a higher incidence of infections and infestations compared to patients treated withchemotherapy alone. There were no differences reported for the incidence of anaemia. Some cases of lateneutropenia occurring more than four weeks after the last infusion of MabThera were reported.

In studies of MabThera in patients with Waldenstrom’s macroglobulinaemia, transient increases inserum IgM levels have been observed following treatment initiation, which may be associated withhyperviscosity and related symptoms. The transient IgM increase usually returned to at least baselinelevel within 4 months.

Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% ofpatients with the most frequently reported events being hypotension and hypertension. Cases of grade 3or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris duringinfusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders wascomparable between patients treated with MabThera and observation. Cardiac events were reported asserious adverse reactions (including atrial fibrillation, myocardial infarction, left ventricular failure,myocardial ischemia) in 3% of patients treated with MabThera compared to < 1% on observation. Instudies evaluating MabThera in combination with chemotherapy, the incidence of grade 3 and 4 cardiacarrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrialflutter/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 infusion orwere associated with predisposing conditions such as fever, infection, acute myocardial infarction orpre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOPgroup was observed in the incidence of other grade 3 and 4 cardiac events including heart failure,myocardial disease and manifestations of coronary artery disease.

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

During the treatment period (induction treatment phase comprising of R-CHOP for at most eightcycles), four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experiencedthromboembolic cerebrovascular accidents during the first treatment cycle. There was no differencebetween the treatment groups in the incidence of other thromboembolic events. In contrast, threepatients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during thefollow-up period.

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

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving

MabThera for treatment of non-Hodgkin’s lymphoma (NHL). In the majority of these cases, MabTherawas administered with chemotherapy.

In the clinical trial evaluating MabThera maintenance treatment in relapsed/refractory follicularlymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after inductiontreatment in both the observation and the MabThera groups. In the observation group, the median IgGlevel subsequently increased to above the LLN, but remained constant in the MabThera group. Theproportion of patients with IgG levels below the LLN was about 60% in the MabThera group throughoutthe 2-year treatment period, while it decreased in the observation group (36% after 2 years).

Toxic Epidermal Necrolysis (Lyell Syndrome) and Stevens-Johnson syndrome, some with fataloutcome, have been reported very rarely.

Patient subpopulations - MabThera monotherapy

Elderly (65 years and above):

The incidence of adverse reactions of all grades and grade 3/4 adverse reactions was similar in elderlypatients compared to younger patients (below 65 years).

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

The percentage of patients reporting adverse reactions upon re-treatment with further courses of

MabThera was similar to the percentage of patients reporting adverse reactions upon initial exposure(any grade and grade 3/4 adverse reactions).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Limited experience with doses higher than the approved dose of intravenous MabThera formulation isavailable from clinical trials in humans. The highest intravenous dose of MabThera tested in humans todate is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. No additionalsafety signals were identified.

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

Three patients in the MabThera subcutaneous formulation trial SABRINA (BO22334) wereinadvertently administered subcutaneous formulation through the intravenous route up to a maximumrituximab dose of 2780 mg with no untoward effect.

Patients who experience overdose or medication error should be closely monitored.

In the post-marketing setting five cases of MabThera overdose have been reported. Three cases had noreported adverse event. The two adverse events that were reported were flu-like symptoms, with a doseof 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drug conjugates,

ATC code: L01FA01

MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), anenzyme used to increase the dispersion and absorption of co-administered substances whenadministered subcutaneously.

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-cellnon-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 andis not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen and, thus, doesnot compete for antibody binding.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain canrecruit immune effector functions to mediate B-cell lysis. Possible mechanisms of effector-mediated celllysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, andantibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on thesurface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on Blymphocytes 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. Inpatients treated for haematological malignancies, B-cell recovery began within 6 months of treatment andgenerally returned to normal levels within 12 months after completion of therapy, although in somepatients this may take longer (up to a median recovery time of 23 months post-induction therapy). Inrheumatoid arthritis patients, immediate depletion of B-cells in the peripheral blood was observedfollowing two infusions of 1000 mg MabThera separated by a 14-day interval. Peripheral blood B-cellcounts begin to increase from Week 24 and evidence for repopulation is observed in the majority ofpatients by Week 40, whether MabThera was administered as monotherapy or in combination withmethotrexate.

Clinical efficacy and safety of MabThera subcutaneous formulation in non-Hodgkin’s lymphoma

The clinical efficacy and safety of MabThera subcutaneous formulation in non-Hodgkin’s lymphoma isbased on data from a phase III clinical trial (SABRINA BO22334) in patients with follicular lymphoma(FL) and a phase Ib dose-finding/dose-confirmation trial (SparkThera BP22333) in patients with FL.

Results from trial BP22333 are presented in section 5.2.

Trial BO22334 (SABRINA)

A two-stage phase III, international, multi-centre, randomised, controlled, open-label trial was conductedin patients with previously untreated follicular lymphoma, to investigate the non-inferiority of thepharmacokinetic profile, together with efficacy and safety of MabThera subcutaneous formulation incombination with CHOP or CVP versus MabThera intravenous formulation in combination with CHOPor CVP.

The objective of the first stage was to establish the rituximab subcutaneous dose that resulted incomparable MabThera subcutaneous formulation serum Ctrough levels compared with MabTheraintravenous formulation, when given as part of induction treatment every 3 weeks (see section 5.2).

Stage 1 enrolled previously untreated patients (n=127) CD20-positive, Follicular Lymphoma (FL)

Grade 1, 2 or 3a.

The objective of stage 2 was to provide additional efficacy and safety data for subcutaneous rituximabcompared with rituximab intravenous using the 1400 mg subcutaneous dose established in stage 1.

Previously untreated patients with CD20-positive, Follicular Lymphoma Grade 1, 2 or 3a (n=283)were enrolled in the stage 2.

The overall trial design was identical among both stages and patients were randomised into thefollowing two treatment groups:

* MabThera subcutaneous formulation (n= 205): first cycle MabThera intravenous formulation plus 7cycles of MabThera subcutaneous formulation in combination with up to 8 cycles of CHOP or CVPchemotherapy administered every 3 weeks.

MabThera intravenous formulation was used at the standard dose of 375 mg/m2 body surface area.

MabThera subcutaneous formulation was given at a fixed dose of 1400 mg.

Patients achieving at least partial response (PR) were entered on the MabThera subcutaneous formulationmaintenance therapy once every 8 weeks for 24 months.

* MabThera intravenous formulation (n= 205): 8 cycles of MabThera intravenous formulation incombination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks.

MabThera intravenous formulation was used at the standard dose of 375 mg/m2.

Patients achieving at least PR were entered on MabThera intravenous formulation maintenance therapyonce every 8 weeks for 24 months.

Key efficacy results for the pooled analysis of 410 patients in SABRINA stages 1 and 2 are shown in

Table 2

Table 2 Efficacy results for SABRINA (BO22334) (Intent to Treat Population)

Pooled Stages 1 & 2

N = 410

Rituximab Rituximabintravenous subcutaneousformulation formulation(n = 205) (n = 205)

Point estimate 84.9% (n = 174) 84.4% (n = 173)

ORR a95% CI [79.2%, 89.5%] [78.7%, 89.1%]

Point estimate 31.7% (n = 65) 32.2% (n = 66)

CRR95% CI [25.4%, 38.6%] [25.9%, 39.1%]

Proportion with PFS event 34.6% (n = 71) 31.7% (n = 65)

PFSb

Hazard ratio (95% CI) 0.90 [0.64%, 1.26%]

ORR - Overall Response Rate

CRR - Complete Response Rate

PFS - Progression-Free Survival (proportion with event, disease progression/relapse or death from any cause)a - at end of Inductionb - at time of final analysis (median follow-up 58 months)

Exploratory analyses showed response rates among BSA, chemotherapy and gender subgroups werenot notably different from the ITT population.

Data from the development programme of MabThera subcutaneous formulation indicate that theformation of anti-rituximab antibodies after subcutaneous administration is comparable with thatobserved after intravenous administration. In the SABRINA trial (BO22334) the incidence oftreatment-induced/enhanced anti-rituximab antibodies was low and similar in the intravenous andsubcutaneous groups (1.9% vs. 2%, respectively). The incidence of treatment-induced/enhancedanti-rHuPH20 antibodies was 8% in the intravenous group compared with 15% in the subcutaneousgroup, and none of the patients who tested positive for anti-rHuPH20 antibodies tested positive forneutralising antibodies.

The overall proportion of patients found to have anti-rHuPH20 antibodies remained generally constantover the follow-up period in both cohorts. The clinical relevance of the development of anti-rituximabantibodies or anti-rHuPH20 antibodies after treatment with MabThera subcutaneous formulation is notknown. There was no apparent impact of the presence of anti-rituximab or anti-rHuPH20 antibodies onsafety or efficacy.

Clinical efficacy and safety of MabThera concentrate for solution for infusion in non-Hodgkin’s lymphoma

Initial treatment in combination with chemotherapy

In an open-label randomised trial, a total of 322 previously untreated patients with follicularlymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2,vincristine 1.4 mg/m2 up to a maximum of 2 mg on Day 1, and prednisolone 40 mg/m2/day on Days1 -5) every 3 weeks for 8 cycles or MabThera 375 mg/m2 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 was53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatmentfailure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumourresponse (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 diseaseprogression or death compared to CVP, 33.6 months and 14.7 months, respectively (p< 0.0001, log-ranktest). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the

CVP group (p < 0.0001, log-rank test).

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

Results from three other randomised trials using MabThera in combination with chemotherapy regimenother than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant improvements inresponse rates, time-dependent parameters as well as in overall survival. Key results from all four trialsare summarised in Table 3.

Table 3 Summary of key results from four phase III randomised trials evaluating the benefitof MabThera with different chemotherapy regimens in follicular lymphoma

Treatment, Median CR, Median OS

Trial FU,

N ORR, % % TTF/PFS/ EFS rates,months mo %

Median TTP: 53-months

CVP, 159 57 10 14.7 71.1

M39021 R-CVP, 162 53 81 41 33.6 80.9

P < 0.0001 p=0.029

Median TTF: 2.6 18-months

CHOP, 205 90 17 years 90

GLSG’00 18

R-CHOP, 223 96 20 Not reached 95p < 0.001 p = 0.01648-months

Median PFS: 28.8

MCP, 96 75 25 74

OSHO-39 47 Not reached

R-MCP, 105 92 50 87p < 0.0001p = 0.0096

CHVP-IFN, 42-months

Median EFS: 36183 85 49

FL2000 42 Not reached 84

R-CHVP-IFN, 94 76 p < 0.0001 91175 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

In a prospective, open label, international, multi-centre, phase III trial 1 193 patients with previouslyuntreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP(n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1 078 patients respondedto induction therapy, of which 1 018 were randomised to MabThera maintenance therapy (n=505) orobservation (n=513). The two treatment groups were well balanced with regards to baselinecharacteristics 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 amaximum period of two years.

The pre-specified primary analysis was conducted at a median observation time of 25 months fromrandomisation, maintenance therapy with MabThera resulted in a clinically relevant and statisticallysignificant improvement in the primary endpoint of investigator assessed progression-free survival (PFS)as compared to observation in patients with previously untreated follicular lymphoma (Table 4).

Significant benefit from maintenance treatment with MabThera was also seen for the secondary endpointsevent-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next chemotherapy(TNCT) and overall response rate (ORR) in the primary analysis (Table 4).

Data from extended follow-up of patients in the study (median follow-up 9 years) confirmed thelong- term benefit of MabThera maintenance therapy in terms of PFS, EFS, TNLT and TNCT (Table 4).

Table 4 Overview of efficacy results for MabThera maintenance vs. observation at theprotocol-defined primary analysis and after 9 years median follow-up (finalanalysis)

Primary analysis Final analysis(median FU: 25 months) (median FU: 9.0 years)

Observation MabThera Observation MabThera

N=513 N=505 N=513 N=505

Primary efficacy

Progression-free survival (median) NR NR 4.06 years 10.49 yearslog-rank p value < 0.0001 < 0.0001hazard ratio (95% CI) 0.50 (0.39, 0.64) 0.61 (0.52, 0.73)risk reduction 50% 39%

Secondary efficacy

Overall survival (median) NR NR NR NRlog-rank p value 0.7246 0.7948hazard ratio (95% CI) 0.89 (0.45, 1.74) 1.04 (0.77, 1.40)risk reduction 11% -6%

Event-free survival (median) 38 months NR 4.04 years 9.25 yearslog-rank p value < 0.0001 < 0.0001hazard ratio (95% CI) 0.54 (0.43, 0.69) 0.64 (0.54, 0.76)risk reduction 46% 36%

TNLT (median) NR NR 6.11 years NRlog-rank p value 0.0003 <0.0001hazard ratio (95% CI) 0.61 (0.46, 0.80) 0.66 (0.55, 0.78)risk reduction 39% 34%

TNCT (median) NR NR 9.32 years NRlog-rank p value 0.0011 0.0004hazard ratio (95% CI) 0.60 (0.44, 0.82) 0.71 (0.59, 0.86)risk reduction 40% 39%

Overall response rate* 55% 74% 61% 79%chi-squared test p value < 0.0001 < 0.0001odds ratio (95% CI) 2.33 (1.73, 3.15) 2.43 (1.84, 3.22)

Complete response (CR/CRu) rate* 48% 67% 53% 72%chi-squared test p value < 0.0001 < 0.0001odds ratio (95% CI) 2.21 (1.65, 2.94) 2.34 (1.80, 3.03)

* at end of maintenance/observation; final analysis results based on median follow-up of 73 months.

FU: follow-up; NR: not reached at time of clinical cut off, TNCT: time to next chemotherapy treatment; TNLT: time to nextanti lymphoma treatment.

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 lesspronounced effect in elderly patients (> 70 years of age), however sample sizes were small.

In a prospective, open label, international, multi-centre, phase III trial, 465 patients withrelapsed/refractory follicular lymphoma were randomised in a first step to induction therapy witheither 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 baselinecharacteristics and disease status. A total of 334 patients achieving a complete or partial remissionfollowing 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/m2 body surface area given every 3 months until disease progression or for amaximum period of two years.

The final efficacy analysis included all patients randomised to both parts of the trial. After a medianobservation time of 31 months for patients randomised to the induction phase, R-CHOP significantlyimproved 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 monthsmedian observation time)

CHOP R-CHOP p-value Risk Reduction1)

Primary efficacy

ORR2) 74% 87% 0.0003 Na

CR2) 16% 29% 0.0005 Na

PR2) 58% 58% 0.9449 Na1) Estimates were calculated by hazard ratios2) Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of CRversus PR versus non-response (p < 0.0001)

Abbreviations: NA, not available; ORR: overall response rate; CR: complete response; PR: partial response

For patients randomised to the maintenance phase of the trial, the median observation time was28 months from maintenance randomisation. Maintenance treatment with MabThera led to a clinicallyrelevant and statistically significant improvement in the primary endpoint, PFS, (time frommaintenance randomisation to relapse, disease progression or death) when compared to observationalone (p< 0.0001 log-rank test). The median PFS was 42.2 months in the MabThera maintenance armcompared to 14.3 months in the observation arm. Using a cox regression analysis, the risk ofexperiencing progressive disease or death was reduced by 61% with MabThera maintenance treatmentwhen compared to observation (95% CI; 45%-72%). Kaplan-Meier estimated progression-free rates at12 months were 78% in the MabThera maintenance group vs. 57% in the observation group. Ananalysis of overall survival confirmed the significant benefit of MabThera maintenance overobservation (p=0.0039 log-rank test). MabThera maintenance treatment reduced the risk of death by56% (95% CI; 22%-75%).

Table 6 Maintenance phase: overview of efficacy results MabThera vs. observation(28 months median observation time)

Efficacy Parameter Kaplan-Meier Estimate of Risk

Median Time to Event (Months) Reduction

Observation MabThera Log-Rank(N = 167) (N=167) p value

Progression-free survival (PFS) 14.3 42.2 < 0.0001 61%

Overall survival NR NR 0.0039 56%

Time to new lymphoma 20.1 38.8 < 0.0001 50%treatment

Disease-free survivala 16.5 53.7 0.0003 67%

PFS

CHOP 11.6 37.5 < 0.0001 71%

R-CHOP 22.1 51.9 0.0071 46%

CR 14.3 52.8 0.0008 64%

PR 14.3 37.8 < 0.0001 54%

OS

CHOP NR NR 0.0348 55%

R-CHOP NR NR 0.0482 56%

NR: not reached; a: only applicable to patients achieving a CR

The benefit of MabThera maintenance treatment was confirmed in all subgroups analysed, regardless ofinduction 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 respondingto CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p< 0.0001) as well as in thoseresponding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). Althoughsubgroups were small, MabThera maintenance treatment provided a significant benefit in terms ofoverall survival for both patients responding to CHOP and patients responding to R-CHOP, althoughlonger 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 (cyclophosphamide750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on Day 1, andprednisolone 40 mg/m2/day on Days 1-5) every 3 weeks for eight cycles, or MabThera 375 mg/m2 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 amedian follow-up duration of approximately 31 months. The two treatment groups were well balanced inbaseline disease characteristics and disease status. The final analysis confirmed that R-CHOP treatmentwas associated with a clinically relevant and statistically significant improvement in the duration ofevent-free survival (the primary efficacy parameter; where events were death, relapse or progression oflymphoma, or institution of a new anti-lymphoma treatment) (p = 0.0001). Kaplan Meier estimates of themedian duration of event-free survival were 35 months in the R-CHOP arm compared to 13 months inthe CHOP arm, representing a risk reduction of 41%. At 24 months, estimates for overall survival were68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequent analysis of the durationof 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 completeresponse 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 patient subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2 microglobulin,

LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow involvement), the riskratios for event-free survival and overall survival (R-CHOP compared with CHOP) were less than 0.83and 0.95 respectively. R-CHOP was associated with improvements in outcome for both high- andlow-risk patients according to age adjusted IPI.

Of 67 patients evaluated for HAMA, no responses were noted. Of 356 patients evaluated for ADA, 1.1%(4 patients) were positive.

The European Medicines Agency has waived the obligation to submit the results of studies withrituximab in all subsets of the paediatric population with follicular lymphoma. See Section 4.2 forinformation on paediatric use.

Rituximab pharmacokinetics following single dose administration of MabThera subcutaneous 375 mg/m2,625 mg/m2 and 800 mg/m2 were compared with MabThera intravenous 375 mg/m2 in FL patients.

Following subcutaneous administration, the absorption of rituximab is slow, reaching maximalconcentrations about 3 days after administration. Based on popPK analysis an absolute bioavailability of71% was estimated. Rituximab exposure increased dose proportional over the 375 mg/m2 to 800 mg/m2subcutaneous dose range. Pharmacokinetic parameters such as clearance, distribution volume, andelimination half-life were comparable for both formulations.

Trial BP22333 (SparkThera)

A two-stage phase Ib trial to investigate the pharmacokinetics, safety and tolerability of MabTherasubcutaneous formulation in patients with follicular lymphoma (FL) as part of maintenance treatment. Instage 2, MabThera subcutaneous formulation at a fixed dose of 1400 mg was administered assubcutaneous injection during maintenance treatment, after at least one cycle of MabThera intravenousformulation to FL patients who had previously responded to MabThera intravenous formulation ininduction.

The comparison of predicted median Cmax data for MabThera subcutaneous formulation andintravenous formulation are summarised in Table 7.

Table 7: Trial BP22333 (SparkThera): Absorption - Pharmacokinetic parameters of

MabThera SC compared to MabThera IV

MabThera MabTherasubcutaneous intravenous

Predicted median Cmax 201 209(q2m) µg/mL

Predicted median Cmax 189 184(q3m) µg/mL

The median Tmax in the MabThera subcutaneous formulation was approximately 3 days as compared tothe Tmax occurring at or close to the end of the infusion for the intravenous formulation.

Trial BO22334 (SABRINA)

MabThera subcutaneous formulation at a fixed dose of 1400 mg was administered for 6 cyclessubcutaneously during induction at 3-weekly intervals, following the first cycle of MabTheraintravenous formulation, in previously untreated FL patients in combination with chemotherapy. Theserum rituximab Cmax at cycle 7 was similar between the two treatment arms, with geometric mean(CV%) values of 250.63 (19.01) μg/mL and 236.82 (29.41) μg/mL for the intravenous and thesubcutaneous formulations respectively, with the resulting geometric mean ratio (Cmax, SC/Cmax, IV) of0.941 (90% CI: 0.872, 1.015).

Geometric mean Ctrough and geometric mean AUCτ from the BP22333 and BO22334 trials aresummarised in Table 8.

Table 8: Distribution/Elimination - Pharmacokinetic parameters of MabThera subcutaneouscompared to MabThera intravenous

Trial BP22333 (SparkThera)

Geometric Geometric Geometric Geometricmean Ctrough mean Ctrough mean AUCτ mean AUCτ(q2m) µg/mL (q3m) µg/mL cycle 2 (q2m) cycle 2 (q3m)µg.day/mL µg.day/mL

MabThera 32.2 12.1 5430 5320subcutaneousformulation

MabThera 25.9 10.9 4012 3947intravenousformulation

Trial BO22334 (SABRINA)

Geometric mean Geometric mean

Ctrough values at pre-dose cycle AUC values at cycle8 µg/mL 7 µg.day/mL

MabThera 134.6 3778subcutaneousformulation

MabThera 83.1 2734intravenousformulation

In a population pharmacokinetic analysis in 403 follicular lymphoma patients who receivedsubcutaneous and/or intravenous MabThera, single or multiple infusions of MabThera as a single agentor in combination with chemotherapy, the population estimates of nonspecific clearance (CL1), initialspecific clearance (CL2) likely contributed by B-cells or tumour burden, and central compartmentvolume of distribution (V1) were 0.194 L/day, 0.535 L/day, and 4.37 L/day, respectively. The estimatedmedian terminal elimination half-life of MabThera subcutaneous formulation was 29.7 days (range, 9.9to 91.2 days). The analysis data set contained 6 003 quantifiable samples from 403 patients administered

SC and/or IV rituximab in trials BP22333 (3 736 samples from 277 patients) and BO22334 (2 267samples from 126 patients). Twenty-nine (0.48%) post-dose observations (all from trial BP22333) werebelow the quantification limit. There were no missing covariate values except baseline B-cell count.

Baseline tumour load was available only in trial BO22334.

In clinical trial BO22334, an effect was observed between body size and exposure ratios reported incycle 7, between rituximab subcutaneous formulation 1400 mg q3w and rituximab intravenousformulation 375 mg/m2 q3w with Ctrough ratios of 2.29, 1.31, and 1.41 in patients with low, mediumand high BSA, respectively (low BSA ≤ 1.70 m2; 1.70 m2 < medium BSA < 1.90 m2; high

BSA ≥ 1.90 m2). The corresponding AUCτ ratios were 1.66, 1.17 and 1.32.

There was no evidence of clinically relevant dependencies of rituximab pharmacokinetics on age andsex.

Anti-rituximab antibodies were detected in only 13 patients and did not result in any clinically relevantincrease in steady-state clearance.

Rituximab has shown to be highly specific to the CD20 antigen on B-cells. Toxicity studies incynomolgus monkeys have shown no other effect than the expected pharmacological depletion of

B-cells in peripheral blood and in lymphoid tissue.

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to 100 mg/kg(treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus due torituximab. However, dose-dependent pharmacologic depletion of B-cells in the lymphoid organs of thefoetuses was observed, which persisted postnatally and was accompanied by a decrease in IgG level inthe newborn animals affected. B-cell counts returned to normal in these animals within 6 months ofbirth and did not compromise the reaction to immunisation.

Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevantfor this molecule. No long-term animal studies have been performed to establish the carcinogenicpotential of rituximab.

Specific studies to determine the effects of rituximab or rHuPH20 on fertility have not been performed.

In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs inmales or females were observed. Additionally, no effects on semen quality were shown for rHuPH20.

In embryofoetal developmental studies in mice, rHuPH20 caused reduced foetal weight and loss ofimplantations at systemic exposures sufficiently in excess of human therapeutic exposure.

There is no evidence of dysmorphogenesis (i.e. teratogenesis) resulting from systemic exposure torHuPH20.

Recombinant human hyaluronidase (rHuPH20)

L-histidine

L-histidine hydrochloride monohydrateα,α-trehalose dihydrate

L-methionine

Polysorbate 80 (E433)

Water for injections

No incompatibilities between MabThera subcutaneous formulation and polypropylene orpolycarbonate syringe material or stainless steel transfer and injection needles and polyethylene

Luer cone stoppers have been observed.

Unopened vial3 years

Once transferred from the vial into the syringe, the solution of MabThera subcutaneous formulation isphysically and chemically stable for 48 hours at 2 °C - 8 °C and subsequently for 8 hours at 30°C indiffuse daylight.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, preparation should take place in controlled and validated aseptic conditions. In-usestorage times and conditions prior to use are the responsibility of the user.

Store in a refrigerator (2 °C - 8 °C). Do not freeze. Keep the vial in the outer carton in order toprotect from light.

For storage conditions after first opening of the medicinal product see section 6.3.

Colourless type I glass vial with butyl rubber stopper with aluminium over seal and a pink plasticflip-off disk, containing 1400 mg/11.7 mL of rituximab.

Each carton contains one vial.

MabThera is provided in sterile, preservative-free, non-pyrogenic, single use vials. Use sterile needleand syringe to prepare MabThera. A peel-off sticker is included on the vials which specifies thestrength, route of administration and indication. This sticker should be removed from the vial and stuckonto the syringe prior to use. The following points should be strictly adhered to regarding the use anddisposal of syringes and other medicinal sharps:

* Needles and syringes should never be reused

* Place all used needles and syringes into a sharps container (puncture-proof disposable container).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/98/067/003

Date of first authorisation: 2 June 1998

Date of latest renewal: 20 May 2008

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/en.