English
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

MabThera (rituximab) – Summary of product characteristics - L01XC02

Updated on site: 08-Oct-2017

Medication nameMabThera
ATC CodeL01XC02
Substancerituximab
ManufacturerRoche Registration Ltd

1.NAME OF THE MEDICINAL PRODUCT

MabThera 100 mg concentrate for solution for infusion

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL contains 10 mg of rituximab.

Each vial contains 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 the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless liquid.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

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 CLL. 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.

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.

Granulomatosis with polyangiitis and microscopic polyangiitis

MabThera, in combination with glucocorticoids, is indicated for the induction of remission in adult patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA).

4.2Posology and method of administration

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

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

In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy. In patients with rheumatoid arthritis, premedication with 100 mg intravenous methylprednisolone

should be completed 30 minutes prior to MabThera infusions to decrease the incidence and severity of infusion related reactions (IRRs).

In patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of MabThera (the last dose of methylprednisolone may be given on the same day as the first infusion of MabThera). This should be followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based on clinical need) during and after MabThera treatment.

Posology

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

Non-Hodgkin’s lymphoma

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/m2 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/m2 body surface area once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum period of two years.

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/m2 body surface area once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum period of two years.

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/m2 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/m2 body surface area, administered as an intravenous infusion once weekly for four weeks (see section 5.1).

Diffuse large B cell non-Hodgkin's lymphoma

MabThera should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of MabThera have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin’s lymphoma.

Dose adjustments during treatment

No dose reductions of MabThera are recommended. When MabThera is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

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 109/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/m2 body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after MabThera infusion.

Rheumatoid arthritis

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

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.

Granulomatosis with polyangiitis and microscopic polyangiitis

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

The recommended dosage of MabThera for induction of remission therapy of granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (four infusions in total).

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with granulomatosis with polyangiitis or microscopic polyangiitis during and following MabThera treatment, as appropriate.

Special populations

Paediatric population

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

Elderly

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

Method of administration

The prepared 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 (IRR) (section 4.8) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.

First infusion

The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.

Subsequent infusions

All indications

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

Rheumatoid arthritis only

Alternative subsequent, faster, infusion schedule

If patients did not experience a serious infusion related reaction with their first or subsequent infusions of a dose of 1000 mg MabThera administered over the standard infusion schedule, a more rapid infusion can be administered for second and subsequent infusions using the same concentration as in previous infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250mg/hour for the first 30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this infusion schedule can be used when administering subsequent infusions.

Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion.

4.3Contraindications

Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease (see section 4.4 regarding other cardiovascular diseases).

4.4Special warnings and precautions for use

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

Progressive multifocal leukoencephalopathy

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

Very rare cases of fatal PML have been reported following use of MabThera. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a Neurologist should be considered as clinically indicated.

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

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

If a patient develops PML, the dosing of 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 related reactions

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

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the 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 of the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first MabThera intravenous infusion. They were characterized by pulmonary events and in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

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

Patients with a high tumour burden or with a high number (≥25 x 109/L) of circulating malignant cells such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome,

should be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 109/L.

Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with 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 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 glucocorticoids, 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 administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion.

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with 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 109/L and/or platelet counts < 75 x 109/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 suggests that MabThera treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with

other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with MabThera. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

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

Immunisations

The safety of immunisation 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-randomised 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. 76% when assessed for >2-fold increase in antibody titer). For CLL patients similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.

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

Skin reactions

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

Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis

Methotrexate (MTX) naïve populations with rheumatoid arthritis

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 (IRRs), which may be related to release of cytokines and/or other chemical mediators. Premedication consisting of an analgesic/anti-pyretic drug and an anti-histaminic drug, should always be administered before each infusion of MabThera. In rheumatoid arthritis premedication with glucocorticoids should also be administered before each infusion of MabThera in order to reduce the frequency and severity of IRRs (see section 4.2 and section 4.8).

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses (see section 4.8). The reactions reported were usually reversible with a reduction in rate, or interruption, of MabThera infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely monitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue MabThera. 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, and those who experienced prior cardiopulmonary adverse reactions, 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.

IRRs for patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to those seen for rheumatoid arthritis patients in clinical trials (see section 4.8).

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a history of cardiac disease should be monitored closely (see Infusion related reactions, above).

Infections

Based on the mechanism of action of MabThera and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infection following MabThera therapy (see section 5.1). 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.

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.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis patients receiving MabThera.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with MabThera. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Late neutropenia

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

Skin reactions

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

Immunisation

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

The safety of immunisation 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 randomised trial, patients with rheumatoid arthritis 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 in rheumatoid arthritis, the proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/sequential use of other DMARDs in rheumatoid arthritis

The concomitant use of MabThera and anti-rheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.

There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following 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.

4.5Interaction with other medicinal products and other forms of interaction

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

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 MabThera.

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.

4.6Fertility, pregnancy and lactation

Contraception in males and females

Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with MabThera.

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 MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons MabThera should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Breast-feeding

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with MabThera and for 12 months following MabThera treatment.

Fertility

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

4.7Effects on ability to drive and use machines

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 MabThera would have no or negligible influence on the ability to drive and use machines.

4.8Undesirable effects

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

Summary of the safety profile

The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with 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 IRRs which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after eight doses of 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 trials in patients with CLL.

The most frequent reported or observed serious adverse drug reactions were:

IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.

Infections, see section 4.4.

Cardiovascular events, see section 4.4.

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

Tabulated list of adverse reactions

The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarised in Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common ( 1/100 to

< 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

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

Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients with NHL and CLL disease treated with MabThera monotherapy/maintenance or in combination with chemotherapy

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Infections and

bacterial

sepsis,

 

serious viral

PML

 

infestations

infections,

+pneumonia,

 

infection2

 

 

 

viral

+febrile infection,

 

Pneumocystis

 

 

 

infections,

+herpes zoster,

 

jirovecii

 

 

 

+bronchitis

+respiratory tract

 

 

 

 

 

 

infection, fungal

 

 

 

 

 

 

infections,

 

 

 

 

 

 

infections of

 

 

 

 

 

 

unknown

 

 

 

 

 

 

aetiology, +acute

 

 

 

 

 

 

bronchitis,

 

 

 

 

 

 

+sinusitis,

 

 

 

 

 

 

hepatitis B1

 

 

 

 

Blood and

neutropenia,

anaemia,

coagulation

 

transient

late neutropenia3

lymphatic

leucopenia,

+pancytopenia,

disorders,

 

increase in

 

system

+febrile

+granulocytopeni

aplastic

 

serum IgM

 

disorders

neutropenia,

a

anaemia,

 

levels3

 

 

+thrombocyt

 

haemolytic

 

 

 

 

openia

 

anaemia,

 

 

 

 

 

 

lymphadenopa

 

 

 

 

 

 

thy

 

 

 

Immune

infusion

hypersensitivity

 

anaphylaxis

tumour lysis

infusion-related

system

related

 

 

 

syndrome,

acute reversible

disorders

reactions4,

 

 

 

cytokine

thrombocytopenia

 

angioedema

 

 

 

release

 

 

 

 

 

 

 

 

 

 

syndrome4,

 

 

 

 

 

 

serum

 

 

 

 

 

 

sickness

 

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Metabolism

 

hyperglycaemia,

 

 

 

 

and nutrition

 

weight decrease,

 

 

 

 

disorders

 

peripheral

 

 

 

 

 

 

oedema, face

 

 

 

 

 

 

oedema,

 

 

 

 

 

 

increased LDH,

 

 

 

 

 

 

hypocalcaemia

 

 

 

 

Psychiatric

 

 

depression,

 

 

 

disorders

 

 

nervousness,

 

 

 

Nervous

 

paraesthesia,

Dysgeusia

 

peripheral

cranial

system

 

hypoaesthesia,

 

 

neuropathy,

neuropathy,

disorders

 

agitation,

 

 

facial nerve

loss of other

 

 

insomnia,

 

 

palsy5

senses5

 

 

vasodilatation,

 

 

 

 

 

 

dizziness, anxiety

 

 

 

 

Eye disorders

 

lacrimation

 

 

severe vision

 

 

 

disorder,

 

 

loss5

 

 

 

conjunctivitis

 

 

 

 

Ear and

 

tinnitus, ear pain

 

 

 

hearing loss5

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

+myocardial

+left

severe cardiac

heart failure4

 

disorders

 

infarction4 and 6,

ventricular

disorders 4 and 6

and 6

 

 

 

arrhythmia,

failure,

 

 

 

 

 

+atrial

+supraventricu

 

 

 

 

 

fibrillation,

lar

 

 

 

 

 

tachycardia,

tachycardia,

 

 

 

 

 

+cardiac disorder

+ventricular

 

 

 

 

 

 

tachycardia,

 

 

 

 

 

 

+angina,

 

 

 

 

 

 

+myocardial

 

 

 

 

 

 

ischaemia,

 

 

 

 

 

 

bradycardia

 

 

 

Vascular

 

hypertension,

 

 

vasculitis

 

disorders

 

orthostatic

 

 

(predominatel

 

 

 

hypotension,

 

 

y cutaneous),

 

 

 

hypotension

 

 

leukocytoclast

 

 

 

 

 

 

ic vasculitis

 

Respiratory,

 

Bronchospasm4,

asthma,

interstitial

respiratory

lung infiltration,

thoracic and

 

respiratory

bronchiolitis

lung disease7

failure4,

 

mediastinal

 

disease, chest

obliterans,

 

 

 

disorders

 

pain, dyspnoea,

lung disorder,

 

 

 

 

 

increased cough,

hypoxia

 

 

 

 

 

rhinitis

 

 

 

 

Gastrointestin

nausea

vomiting ,

abdominal

 

gastro-intestin

 

al disorders

 

diarrhoea,

enlargement

 

al perforation7

 

 

 

abdominal pain,

 

 

 

 

 

 

dysphagia,

 

 

 

 

 

 

stomatitis,

 

 

 

 

 

 

constipation,

 

 

 

 

 

 

dyspepsia,

 

 

 

 

 

 

anorexia, throat

 

 

 

 

 

 

irritation

 

 

 

 

Skin and

pruritus,

urticaria,

 

 

severe bullous

 

subcutaneous

rash,

sweating, night

 

 

skin reactions,

 

tissue

+alopecia

sweats, +skin

 

 

Stevens-Johns

 

disorders

 

disorder

 

 

on syndrome

 

 

 

 

 

 

toxic

 

 

 

 

 

 

epidermal

 

 

 

 

 

 

necrolysis

 

 

 

 

 

 

(Lyell’s

 

 

 

 

 

 

syndrome) 7

 

Musculoskelet

 

hypertonia,

 

 

 

 

al, connective

 

myalgia,

 

 

 

 

tissue and

 

arthralgia, back

 

 

 

 

bone disorders

 

pain, neck pain,

 

 

 

 

 

 

pain

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Renal and

 

 

 

 

renal failure4

 

urinary

 

 

 

 

 

 

disorders

 

 

 

 

 

 

General

fever , chills,

tumour pain,

infusion site

 

 

 

disorders and

asthenia,

flushing, malaise,

pain

 

 

 

administration

headache

cold syndrome,

 

 

 

 

site conditions

 

+fatigue,

 

 

 

 

 

 

+shivering,

 

 

 

 

 

 

+multi-organ

 

 

 

 

 

 

failure4

 

 

 

 

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 infusionrelated 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.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is <1% of patients by the eighth cycle of MabThera (containing) treatment.

Description of selected adverse reactions

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.

Localized 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% 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 haematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses

(Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving 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 MabThera-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. During the treatment course 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. Studies in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1x109/L between day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to day 42) following treatment with MabThera plus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of 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 adverse 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 ischaemia) 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 infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall

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

Respiratory system

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

Neurologic disorders

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

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

Gastrointestinal disorders

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of non-Hodgkin 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).

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

Skin and subcutaneous tissue disorders

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

Patient subpopulations - 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

Elderly patients ( 65 years)

The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (<65 years), with previously untreated or relapsed/refractory CLL.

Experience from rheumatoid arthritis

Summary of the safety profile

The overall safety profile of 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 moderate to 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.

Tabulated list of adverse reactions

Adverse reactions are listed in Table 2. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most frequent adverse reactions considered due to receipt of MabThera were IRRs. The overall incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during the initial course. In addition to adverse reactions seen in RA clinical trials for MabThera, 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

Very Common

Common

Uncommon

Rare

Very rare

Class

 

 

 

 

 

 

 

 

Infections and

upper respiratory

Bronchitis, sinusitis,

 

 

PML, reactivation

Infestations

tract infection,

gastroenteritis, tinea

 

 

of hepatitis B

 

urinary tract

pedis

 

 

 

 

infections

 

 

 

 

Blood and

 

neutropenia1

 

late neutropenia2

Serum

lymphatic

 

 

 

 

sickness-like

system disorders

 

 

 

 

reaction

Cardiac

 

 

 

Angina pectoris,

Atrial flutter

disorders

 

 

 

atrial fibrillation,

 

 

 

 

 

heart failure,

 

 

 

 

 

myocardial

 

 

 

 

 

infarction

 

Immune system

3Infusion related

 

3Infusion

 

 

disorders

reactions

 

related

 

 

General

(hypertension,

 

reactions

 

 

disorders and

nausea, rash,

 

(generalized

 

 

administration

pyrexia, pruritus,

 

oedema,

 

 

site conditions

urticaria, throat

 

bronchospasm,

 

 

 

irritation, hot flush,

 

wheezing,

 

 

 

hypotension,

 

laryngeal

 

 

 

rhinitis, rigors,

 

oedema,

 

 

 

tachycardia,

 

angioneurotic

 

 

 

fatigue,

 

oedema,

 

 

 

oropharyngeal

 

generalized

 

 

 

pain, peripheral

 

pruritus,

 

 

 

oedema, erythema)

 

anaphylaxis,

 

 

 

 

 

anaphylactoid

 

 

 

 

 

reaction)

 

 

Metabolism and

 

hypercholesterolemia

 

 

 

nutritional

 

 

 

 

 

disorders

 

 

 

 

 

Nervous system

headache

paraesthesia,

 

 

 

disorders

 

migraine, dizziness,

 

 

 

 

 

sciatica

 

 

 

Skin and

 

alopecia

 

 

Toxic Epidermal

subcutaneous

 

 

 

 

Necrolysis

tissue disorders

 

 

 

 

(Lyell’s

 

 

 

 

 

syndrome),

 

 

 

 

 

Stevens-Johnson

 

 

 

 

 

syndrome5

Psychiatric

 

depression, anxiety

 

 

 

disorders

 

 

 

 

 

Gastrointestinal

 

Dyspepsia,

 

 

 

disorders

 

diarrhoea,

 

 

 

 

 

gastro-oesophageal

 

 

 

 

 

reflux, mouth

 

 

 

 

 

ulceration, upper

 

 

 

 

 

abdominal pain

 

 

 

Musculo skeletal

 

arthralgia /

 

 

 

disorders

 

musculoskeletal

 

 

 

 

 

pain, osteoarthritis,

 

 

 

 

 

bursitis

 

 

 

Investigations

decreased IgM

decreased IgG

 

 

 

 

levels4

levels4

 

 

 

1 Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials 2 Frequency category derived from post-marketing data.

3 Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRs may occur as a result of hypersensitivity and/or to the mechanism of action.

4 Includes observations collected as part of routine laboratory monitoring. 5 Includes fatal cases

Multiple courses

Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs following first MabThera exposure was highest during the first 6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the first treatment course), RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.

Infusion-related reactions

The most frequent ADRs following receipt of MabThera in clinical studies were 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 declined with subsequent infusions. In clinical trials fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Severe IRRs with fatal outcome have been reported in the post-marketing setting.

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

Description of selected adverse reactions

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 antibiotics 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.

In patients with non-Hodgkin’s lymphoma receiving MabThera 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 adverse reactions

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

Neurologic events

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

Neutropenia

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

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

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported in the post-marketing setting, some of which were associated with fatal infections.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Laboratory abnormalities

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

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

Experience from granulomatosis with polyangiitis and microscopic polyangiitis

In the clinical trial in granulomatosis with polyangiitis and microscopic polyangitis, 99 patients were treated with MabThera (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1).

Tabulated list of adverse reactions

The ADRs listed in Table 3 were all adverse events which occurred at an incidence of 5% in the MabThera group.

Table 3 Adverse drug reactions occurring at 6-months in ≥ 5% of patients receiving MabThera, and at a higher frequency than the comparator group, in the pivotal clinical study.

Body system

Rituximab

Adverse event

(n=99)

Blood and lymphatic

 

system disorders

 

Thrombocytopenia

7%

Gastrointestinal

 

disorders

 

Diarrhoea

18%

Dyspepsia

6%

Constipation

5%

General disorders and

 

administration site conditions

 

Peripheral oedema

16%

Immune system disorders

 

Cytokine release syndrome

5%

Body system

Rituximab

Adverse event

(n=99)

Infections and infestations

 

Urinary tract infection

7%

Bronchitis

5%

Herpes zoster

5%

Nasopharyngitis

5%

Investigations

 

Decreased haemoglobin

6%

Metabolism and nutrition disorders

 

Hyperkalaemia

5%

Musculoskeletal and connective

 

tissue disorders

 

Muscle spasms

18%

Arthralgia

15%

Back pain

10%

Muscle weakness

5%

Musculoskeletal pain

5%

Pain in extremities

5%

Nervous system disorders

 

Dizziness

10%

Tremor

10%

Psychiatric disorders

 

Insomnia

14%

Respiratory, thoracic and

 

mediastinal disorders

 

Cough

12%

Dyspnoea

11%

Epistaxis

11%

Nasal congestion

6%

Skin and subcutaneous

 

tissue disorders

 

Acne

7%

Vascular disorders

 

Hypertension

12%

Flushing

5%

Selected adverse drug reactions

Infusion related reactions

IRRs in the GPA and MPA clinical trial were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators in the safety population. Ninety nine patients were treated with MabThera and 12% experienced at least one IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing, throat irritation, and tremor. MabThera was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.

Infections

In the 99 MabThera patients, the overall rate of infection was approximately 237 per 100 patient years (95% CI 197 - 285) at the 6-month primary endpoint. Infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections.

The rate of serious infections was approximately 25 per 100 patient years. The most frequently reported serious infection in the MabThera group was pneumonia at a frequency of 4%.

Malignancies

The incidence of malignancy in MabThera treated patients in the granulomatosis with polyangiitis and microscopic polyangiitis clinical study was 2.00 per 100 patient years at the study common closing date (when the final patient had completed the follow-up period). On the basis of standardized incidence ratios, the incidence of malignancies appears to be similar to that previously reported in patients with ANCA-associated vasculitis.

Cardiovascular adverse reactions

Cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149-470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI 3 -15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see Section 4.4).

Neurologic events

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

Hepatitis-B reactivation

A small number of cases of hepatitis-B reactivation, some with fatal outcome, have been reported in granulomatosis with polyangiitis and microscopic polyangiitis patients receiving MabThera in the postmarketing setting.

Hypogammaglobulinaemia

Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in granulomatosis with polyangiitis and microscopic polyangiitis patients treated with MabThera. At 6 months, in the active-controlled, randomised, double-blind, multicenter, non-inferiority trial, in the MabThera group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the cyclophosphamide group. There was no increased rate in overall infections or serious infections in patients with low IgA, IgG or IgM.

Neutropenia

In the active-controlled, randomised, double-blind, multicenter, non-inferiority trial of MabThera in granulomatosis with polyangiitis and microscopic polyangiitis, 24% of patients in the MabThera group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in MabThera-treated patients. The effect of multiple MabThera courses on the development of neutropenia in granulomatosis with polyangiitis and microscopic polyangiitis patients has not been studied in clinical trials.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Reporting of suspected adverse reactions

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

4.9Overdose

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

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

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

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, 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 Fc 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 haematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg 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. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of MabThera. In patients with granulomatosis with polyangiitis or microscopic polyangiitis, the number of peripheral blood B cells decreased to <10 cells/μL after two weekly infusions of rituximab 375 mg/m2, and remained at that level in most patients up to the 6 month timepoint. The majority of patients (81%) showed signs of B cell return, with counts >10 cells/μL by month 12, increasing to 87% of patients by month 18.

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

Follicular lymphoma

Monotherapy

Initial treatment, weekly for 4 doses

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL received 375 mg/m2 of MabThera as an intravenous infusion once weekly for four weeks. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI95 % 41 % - 56 %) with a 6 % complete response (CR) and a 42 % partial response (PR) rate. The projected median time to progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58 % vs. 12 %), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53 % vs. 38 %), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response < 3 months) relapse (50 % vs. 22 %). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78 % versus 43 % in patients with no ABMT. Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) on response to 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 trial, 37 patients with relapsed or chemoresistant, low grade or follicular B cell NHL received 375 mg/m2 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 trials, 39 patients with relapsed or chemoresistant, bulky disease (single lesion 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m2 of MabThera as intravenous infusion weekly for four doses. The ORR was 36 % (CI95 % 21 % – 51 %; CR 3 %, PR 33 %) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

Re-treatment, weekly for 4 doses

In a multi-centre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular B cell NHL, who had achieved an objective clinical response to a prior course of MabThera, were re-treated with 375 mg/m2 of MabThera as intravenous infusion weekly for four doses. Three of the patients had received two courses of MabThera before enrolment and thus were given a third course in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORR was 38 % (CI95 % 26 % – 51 %; 10 % CR, 28 % PR) with a projected median TTP for responding patients of 17.8 months (range 5.4 – 26.6). This compares favourably with the TTP achieved after the prior course of 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/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1 -5) every 3 weeks for 8 cycles or 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 was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to

treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p< 0.0001 Chi-Square test) in the R-CVP group (80.9 %) than the CVP group (57.2 %). Treatment with R-CVP significantly prolonged the time to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively

(p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test).

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

Results from three other randomised trials using 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 4.

Table 4 Summary of key results from four phase III randomised studies evaluating the benefit of MabThera with different chemotherapy regimens in follicular lymphoma

 

Treatment,

Median

 

CR,

Median

OS

Study

FU,

ORR, %

TTF/PFS/ EFS

rates,

N

%

 

months

 

mo

%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Median TTP:

53-months

M39021

CVP, 159

14.7

71.1

R-CVP, 162

33.6

80.9

 

 

 

 

 

P<0.0001

p=0.029

 

 

 

 

 

 

 

 

 

 

 

 

Median TTF: 2.6

18-months

GLSG’00

CHOP, 205

years

R-CHOP, 223

Not reached

 

 

 

 

 

 

 

p < 0.001

p = 0.016

 

 

 

 

 

 

 

 

 

 

 

 

Median PFS: 28.8

48-months

 

MCP, 96

 

OSHO 39

Not reached

 

 

 

-

R-MCP, 105

 

p < 0.0001

 

p = 0.0096

 

CHVP-IFN,

 

 

 

Median EFS: 36

42-months

 

 

FL2000

Not reached

R-CHVP-IFN,

 

 

p < 0.0001

 

 

 

 

p = 0.029

 

 

 

 

 

 

 

 

 

 

 

 

EFS – Event Free Survival

TTP – Time to progression or death

PFS – Progression-Free Survival

TTF – Time to Treatment Failure

OS rates – survival rates at the time of the analyses

Maintenance therapy

Previously untreated follicular lymphoma

In a prospective, open label, international, multi-centre, phase III trial 1193 patients with previously untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP (n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1078 patients responded to induction therapy, of which 1018 were randomised to 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.

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 observation in patients with previously untreated follicular lymphoma (Table 5).

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 5). The results of the primary analysis were confirmed with longer follow-up (median observation time: 48 months and 73 months), and have been added to Table 5 to show the comparison between the 25 and 48 and 73 month follow up periods.

Table 5 Maintenance phase: overview of efficacy results MabThera vs. observation after 73 months median observation time (compared with results of primary analysis based on 25 months median observation time, and updated analysis based on 48 months median observation time)

 

Observation

MabThera

Log rank P

Risk reduction

 

N=513

N=505

value

 

 

 

 

 

Primary efficacy

 

 

 

 

PFS (median)

48.5 months

NR

<0.0001

42%

 

[48.4 months]

[NR]

[<0.0001]

[45%]

 

(NR)

(NR)

(<0.0001)

(50%)

Secondary efficacy

 

 

 

 

EFS (median)

48.4 months

NR

<0.0001

39%

 

[47.6 months]

[NR]

[< 0.0001]

[42%]

 

(37.8 months)

(NR)

(< 0.0001)

(46%)

OS (median)

NR

NR

0.8959

2%

 

[NR]

[NR]

[0.9298]

[ 2%]

 

(NR)

(NR)

(0.7246)

(11%)

TNLT (median)

71.0 months

NR

<0.0001

37%

 

[60.2 months]

[NR]

[<0.0001]

[39%]

 

(NR)

(NR)

(0.0003)

(39%)

TNCT (median)

85.1 months

NR

0.0006

30%

 

[NR]

[NR]

[0.0006]

[34%]

 

(NR)

(NR)

(0.0011)

(40%)

ORR*

60.7%

79.0%

<0.0001#

OR=2.43

 

[60.7%]

[79.0%]

[<0.0001#]

[OR=2.43]

 

(55.0%)

(74.0%)

(< 0.0001)

(OR =2.33)

Complete response

52.7%

66.8%

<0.0001

OR=2.34

(CR/CRu) rate*

[52.7%]

[72.2%]

[<0.0001]

[OR=2.34]

 

(47.7%)

(66.8%)

(< 0.0001)

[ (OR = 2.21)

*At end of maintenance/observation; # p values from chi-squared test

Main values correspond to 73 months median observation time, italicized values in brackets correspond to 48 months median observation time, and values in parentheses correspond to 25 months median observation time (primary analysis). 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, OR: odds ratio.

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/m2 body surface area given every 3 months until disease progression or for a maximum period of two years.

The final efficacy analysis included all patients randomised to both parts of the study. After a median observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to CHOP (see Table 6).

Table 6 Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months median observation time)

 

CHOP

R CHOP

p value

Risk Reduction1)

Primary efficacy

 

 

 

 

ORR2)

74 %

87 %

0.0003

Na

CR2)

16 %

29 %

0.0005

Na

PR2)

58 %

58 %

0.9449

Na

1)Estimates were calculated by hazard ratios

2)Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of CR versus PR versus non-response (p < 0.0001)

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

For patients randomised to the maintenance phase of the trial, the median observation time was 28 months from maintenance randomisation. Maintenance treatment with 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 7 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 %

Subgroup analysis

 

 

 

 

PFS

 

 

 

 

CHOP

11.6

37.5

< 0.0001

71 %

R-CHOP

22.1

51.9

0.0071

46 %

CR

14.3

52.8

0.0008

64 %

PR

14.3

37.8

< 0.0001

54 %

OS

 

 

 

 

CHOP

NR

NR

0.0348

55 %

R-CHOP

NR

NR

0.0482

56 %

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

The benefit of 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 7). 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 overall survival for both patients responding to CHOP and patients responding to R-CHOP, although longer follow-up is required to confirm this observation.

Diffuse large B cell non-Hodgkin’s lymphoma

In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years) with diffuse large B cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1-5) every 3 weeks for eight cycles, or 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 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 randomised trials, a total of 817 previously untreated patients and 552 patients with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or MabThera in combination with FC (R-FC). MabThera was administered at a dosage of 375 mg/m2 during the first cycle one day prior to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had previously been treated with monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 8a and Table 8b) and 552 patients (276 R-FC, 276 FC) for the relapsed/refractory study (Table 9) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p = 0.0319, log-rank test) (Table 8a). The benefit in terms of PFS was consistently observed in most patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 8b).

Table 8a First-line treatment of chronic lymphocytic leukaemia

Overview of efficacy results for MabThera plus FC vs. FC alone - 48.1 months median observation time

Efficacy Parameter

Kaplan-Meier Estimate of

Risk

 

Median Time to Event (Months)

Reduction

 

FC

R-FC

Log-Rank

 

 

(N = 409)

(N=408)

p value

 

Progression free survival (PFS)

32.8

55.3

<0.0001

45%

Overall survival

NR

NR

0.0319

27%

Event free survival

31.3

51.8

<0.0001

44%

Response rate (CR, nPR, or PR)

72.6%

85.8%

<0.0001

n.a.

CR rates

16.9%

36.0%

<0.0001

n.a.

Duration of response*

36.2

57.3

<0.0001

44%

Disease free survival (DFS)**

48.9

60.3

0.0520

31%

Time to new treatment

47.2

69.7

<0.0001

42%

 

 

 

 

 

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

**: only applicable to patients achieving a CR

Table 8b First-line treatment of chronic lymphocytic leukaemia

Hazard ratios of progression-free survival according to Binet stage (ITT) – 48.1 months median observation time

Progression free survival (PFS)

Number of

Hazard Ratio

p-value (Wald

 

patients

(95% CI)

test, not

 

FC

R FC

 

adjusted)

Binet stage A

0.39 (0.15; 0.98)

0.0442

Binet stage B

0.52 (0.41; 0.66)

<0.0001

Binet stage C

0.68 (0.49; 0.95)

0.0224

CI: Confidence Interval

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

Table 9 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

Risk

 

Median Time to Event (Months)

Reduction

 

FC

R-FC

Log-Rank

 

 

(N = 276)

(N=276)

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.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with MabThera in all subsets of the paediatric population with follicular lymphoma and CLL. See Section 4.2 for information on paediatric use.

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-inhibitors was demonstrated in a pivotal randomised, controlled, double-blind, multicenter trial (Trial 1).

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one or more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to the criteria of the American College of Rheumatology (ACR). 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 MabThera between weeks 24 and 56, under an open label extension study protocol.

Trials of MabThera 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 MabThera treatment are insufficient, in particular concerning the risk of development of malignancies and PML.

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 10). 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 10 Clinical response outcomes at primary endpoint in Trial 1(ITT population)

 

Outcome†

Placebo+MTX

MabThera+MTX

 

 

 

 

(2 x 1000 mg)

Trial 1

 

N= 201

N= 298

 

 

 

 

 

 

ACR20

(18%)

153 (51%)***

 

ACR50

11 (5%)

80 (27%)***

 

ACR70

(1%)

37 (12%)***

 

EULAR Response

(22%)

193 (65%)***

 

(Good/Moderate)

 

 

 

 

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 10).

Radiographic response

Structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.

In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitor therapies, receiving 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 MabThera 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 11).

Table 11 Radiographic outcomes at 1 year (mITT population)

 

Placebo+MTX

MabThera+MTX

 

 

2 × 1000 mg

 

 

 

Trial 1

(n = 184)

(n = 273)

Mean change from baseline:

 

1.01*

Modified total sharp score

2.30

Erosion score

1.32

0.60*

Joint space narrowing score

0.98

0.41**

Proportion of patients with no radiographic

46%

53%, NS

change

 

 

Proportion of patients with no erosive change

52%

60%, NS

 

 

 

150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX by one year * p <0.05, ** p < 0.001. Abbreviation: NS, non significant

Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis at 2 years in Trial 1 demonstrated significantly reduced progression of structural joint damage in patients receiving 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 MabThera 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 12).

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 12).

Table 12 Physical Function and Quality of Life outcomes at week 24 in Trial 1

Outcome†

 

Placebo+MTX

MabThera+MTX

 

 

 

(2 x 1000 mg)

 

 

n=201

n=298

Mean change in HAQ DI

0.1

 

0.4***

% HAQ DI MCID

-

20%

-

51%

0.5

9.1

***

Mean change in FACIT T

 

 

-

 

n=197

n=294

 

 

 

 

**

Mean Change in SF 36 PHS

0.9

5.8***

% SF 36 PHS MCID

 

13%

48%***

Mean change in SF 36 MHS

1.3

 

4.7

 

% SF 36 MHS MCID

 

20%

38%*

† Outcome at 24 weeks

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

Efficacy in autoantibody (RF and or anti-CCP) seropositive patients

Patients seropositive to Rheumatoid Factor (RF) and/or anti- Cyclic Citrullinated Peptide (anti-CCP) who were treated with 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 13). 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 13 Summary of efficacy by baseline autoantibody status

 

Week 24

Week 48

 

Seropositive

Seronegative

Seropositive

Seronegative

 

(n=514)

(n=106)

(n=506)

(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.

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)

 

 

 

 

patients

ACR50

 

ACR20

 

 

 

of

ACR70

%

 

 

 

 

 

 

 

 

1st

2nd

3rd

4th

Course

Course

Course

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.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with MabThera in all subsets of the paediatric population with autoimmune arthritis. See Section 4.2 for information on paediatric use.

Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis

A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis (75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator, randomised, double-blind, multicenter, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2mg/kg/day) for 3-6 months or MabThera (375 mg/m2) once weekly for 4 weeks. All patients in the cyclophosphamide arm received azathioprine maintenance therapy in during follow-up. Patients in both arms received 1000mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day). Prednisone tapering was to be completed by 6 months from the start of trial treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%. The trial demonstrated non-inferiority of MabThera to cyclophosphamide for complete remission (CR) at 6 months (Table 14).

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing disease (Table 15).

Table 14 Percentage of patients who cchieved complete remission at 6 months (Intent-to-treat population*)

 

 

 

 

 

MabThera

Cyclophosphamide

 

Treatment Difference

 

 

 

 

 

(n 99)

 

(n 98)

 

 

(MabThera-

 

 

 

 

 

 

 

 

 

 

Cyclophosphamide)

 

 

 

 

 

 

 

 

 

 

 

 

Rate

 

 

63.6%

53.1%

 

10.6%

 

 

 

 

 

 

 

 

 

 

95.1%b CI

 

 

 

 

 

 

 

 

 

 

( 3.2%, 24.3%) a

 

 

 

 

 

 

 

 

 

 

 

 

CI = confidence interval.

 

 

 

 

 

 

 

* Worst case imputation

lower bound ( 3.2%) was higher than the pre-determined

 

a Non-inferiority was

demonstrated since the

 

non-inferiority margin ( 20%).

 

 

 

 

 

 

b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.

Table 15 Complete remission at 6-months by disease status

 

 

 

 

 

 

 

MabThera

 

Cyclophosphamide

 

Difference (CI 95%)

 

All patients

 

n=99

 

n=98

 

 

 

Newly diagnosed

 

n=48

 

n=48

 

 

 

Relapsing

 

n=51

 

n=50

 

 

 

Complete remission

 

 

 

 

 

 

All Patients

 

63.6%

 

53.1%

 

 

10.6% ( 3.2, 24.3)

 

Newly diagnosed

 

60.4%

 

64.6%

 

 

− 4.2% (− 23.6, 15.3)

 

Relapsing

 

66.7%

 

42.0%

 

 

24.7% (5.8, 43.6)

Worst case imputation is applied for patients with missing data

Complete remission at 12 and 18 months

In the MabThera group, 48% of patients achieved CR at 12 months, and 39% of patients achieved CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the MabThera group compared with four in the cyclophosphamide group.

Retreatment with MabThera

Based upon investigator judgment, 15 patients received a second course of MabThera therapy for treatment of relapse of disease activity which occurred between 6 and 18 months after the first course of MabThera. The limited data from the present trial preclude any conclusions regarding the efficacy of subsequent courses of MabThera in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses (i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with MabThera has been achieved, continued immunosuppressive therapy may be considered to prevent relapse. The efficacy and safety of MabThera in maintenance therapy has not been established.

Laboratory evaluations

A total of 23/99 (23%) MabThera-treated patients in the trial tested positive for HACA by 18 months. None of the 99 MabThera-treated patients were HACA positive at screening. The clinical relevance of HACA formation in MabThera-treated patients is unclear.

5.2Pharmacokinetic properties

Non-Hodgkin’s lymphoma

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

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

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

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

Chronic lymphocytic leukaemia

MabThera was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to 500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL patients. The mean Cmax (N=15) was 408 µg/mL (range, 97 – 764 µg/mL) after the fifth 500 mg/ m2 infusion and the mean terminal half-life was 32 days (range, 14 – 62 days).

Rheumatoid arthritis

Following two intravenous infusions of MabThera at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day (range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 l (range, 1.7 to

7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSA and gender were the most significant covariates to explain inter-individual variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic differences are not considered to be clinically relevant and dose adjustment is not required. No pharmacokinetic data are available in patients with hepatic or renal impairment.

The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first infusion ranged from 157 to 171 g/mL for 2 x 500 mg dose and ranged from 298 to 341 g/mL for 2 x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 g/mL for the

2 500 mg dose and ranged from 355 to 404 g/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 Cmax was 16 to 19% higher following second infusion compared to the first infusion for both doses.

The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was

170 to 175 g/mL for 2 x 500 mg dose and 317 to 370 g/mL for 2 x 1000 mg dose. Cmax following second infusion, was 207 g/mL for the 2 x 500 mg dose and ranged from 377 to 386 g/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 g/mL and a mean terminal half-life of 19.2 days.

Granulomatosis with polyangiitis and microscopic polyangiitis

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

5.3Preclinical safety data

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

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to

100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the foetuses was observed, which persisted 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 immunisation.

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

Specific studies to determine the effects of rituximab on fertility have not been performed. In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or females were observed.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Sodium citrate

Polysorbate 80

Sodium chloride

Sodium hydroxide

Hydrochloric acid

Water for injections

6.2Incompatibilities

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

6.3Shelf life

Unopened vial 30 months

Diluted product

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.

6.4Special precautions for storage

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

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

6.5Nature 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.

6.6Special precautions for disposal and other handling

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 discolouration prior to administration.

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

7.MARKETING AUTHORISATION HOLDER

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/98/067/001

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 2 June 1998

Date of latest renewal: 2 June 2008

10.DATE OF REVISION OF THE TEXT

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

1. NAME OF THE MEDICINAL PRODUCT

MabThera 500 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL contains 10 mg of rituximab.

Each vial contains 500 mg of rituximab.

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 CLL. 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.

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.

Granulomatosis with polyangiitis and microscopic polyangiitis

MabThera, in combination with glucocorticoids, is indicated for the induction of remission in adult patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA).

4.2 Posology and method of administration

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

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

In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy.

In patients with rheumatoid arthritis, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to MabThera infusions to decrease the incidence and severity of infusion related reactions (IRRs).

In patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of MabThera (the last dose of methylprednisolone may be given on the same day as the first infusion of MabThera). This should be followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based on clinical need) during and after MabThera treatment.

Posology

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

Non-Hodgkin’s lymphoma

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/m2 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/m2 body surface area once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum period of two years.

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/m2 body surface area once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum period of two years.

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/m2 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/m2 body surface area, administered as an intravenous infusion once weekly for four weeks (see section 5.1).

Diffuse large B cell non-Hodgkin's lymphoma

MabThera should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of MabThera have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin’s lymphoma.

Dose adjustments during treatment

No dose reductions of MabThera are recommended. When MabThera is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

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 109/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/m2 body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after MabThera infusion.

Rheumatoid arthritis

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

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.

Granulomatosis with polyangiitis and microscopic polyangiitis

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

The recommended dosage of MabThera for induction of remission therapy of granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (four infusions in total).

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with granulomatosis with polyangiitis or microscopic polyangiitis during and following MabThera treatment, as appropriate.

Special populations

Paediatric population

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

Elderly

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

Method of administration

The prepared 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 IRRs (section 4.8) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.

First infusion

The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.

Subsequent infusions

All indications

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

Rheumatoid arthritis only

Alternative subsequent, faster, infusion schedule

If patients did not experience a serious infusion related reaction with their first or subsequent infusions of a dose of 1000 mg MabThera administered over the standard infusion schedule, a more rapid infusion can be administered for second and subsequent infusions using the same concentration as in previous infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250mg/hour for the first 30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this infusion schedule can be used when administering subsequent infusions.

Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion.

4.3 Contraindications

Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease (see section 4.4 regarding other cardiovascular diseases).

4.4 Special warnings and precautions for use

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

Progressive multifocal leukoencephalopathy

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

Very rare cases of fatal PML have been reported following the use of MabThera. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a Neurologist should be considered as clinically indicated.

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

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

If a patient develops PML the dosing of 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 related reactions

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

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the 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 of the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first MabThera intravenous infusion. They were characterized by pulmonary events and in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

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

Patients with a high tumour burden or with a high number (≥25 x 109/L) of circulating malignant cells such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome,

should be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 109/L.

Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with 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 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 glucocorticoids, 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 administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion.

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with 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 109/L and/or platelet counts < 75 x 109/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 suggests that MabThera treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be

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

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

Immunisations

The safety of immunisation 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- randomised 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. 76% when assessed for >2-fold increase in antibody titer). For CLL patients similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.

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

Skin reactions:

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

Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis

Methotrexate (MTX) naïve populations with rheumatoid arthritis

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 (IRRs), which may be related to release of cytokines and/or other chemical mediators. Premedication consisting of an analgesic/anti-pyretic drug and an anti-histaminic drug, should always be administered before each infusion of MabThera. In rheumatoid arthritis premedication with glucocorticoids should also be administered before each infusion of MabThera in order to reduce the frequency and severity of IRRs (see section 4.2 and section 4.8).

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses (see section 4.8). The reactions reported were usually reversible with a reduction in rate, or interruption, of MabThera infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely monitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue MabThera. 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, and those who experienced prior cardiopulmonary adverse reactions 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.

IRRs for patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to those seen for rheumatoid arthritis patients in clinical trials (see section 4.8).

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a history of cardiac disease should be monitored closely (see Infusion related reactions, above).

Infections

Based on the mechanism of action of MabThera and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infection following MabThera therapy (see section 5.1). 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.

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.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis patients receiving MabThera.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guideline. Patients with active hepatitis B disease should not be treated with MabThera.Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Late neutropenia

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

Skin reactions

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

Immunisation

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

The safety of immunisation 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 randomised trial, patients with rheumatoid arthritis 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 in rheumatoid arthritis, the proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/sequential use of other DMARDs in rheumatoid arthritis

The concomitant use of MabThera and anti-rheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.

There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following 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.

4.5 Interaction with other medicinal products and other forms of interaction

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

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 MabThera.

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.

4.6 Fertility, pregnancy and lactation

Contraception in males and females

Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with MabThera.

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 MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons MabThera should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Breast-feeding

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with MabThera and for 12 months following MabThera treatment.

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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

Summary of the safety profile

The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with 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 IRRs which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after eight doses of 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 trials in patients with CLL

The most frequent reported or observed serious adverse drug reactions were:

IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.

Infections, see section 4.4.

Cardiovascular events, see section 4.4.

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

Tabulated list of adverse reactions

The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarised in Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common ( 1/100 to

< 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

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

Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients with NHL and CLL disease treated with MabThera monotherapy/maintenance or in combination with chemotherapy

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Infections and

bacterial

sepsis,

 

serious viral

PML

 

infestations

infections,

+pneumonia,

 

infection2

 

 

 

viral

+febrile infection,

 

Pneumocystis

 

 

 

infections,

+herpes zoster,

 

jirovecii

 

 

 

+bronchitis

+respiratory tract

 

 

 

 

 

 

infection, fungal

 

 

 

 

 

 

infections,

 

 

 

 

 

 

infections of

 

 

 

 

 

 

unknown

 

 

 

 

 

 

aetiology, +acute

 

 

 

 

 

 

bronchitis,

 

 

 

 

 

 

+sinusitis,

 

 

 

 

 

 

hepatitis B1

 

 

 

 

Blood and

neutropenia,

anaemia,

coagulation

 

transient

late neutropenia3

lymphatic

leucopenia,

+pancytopenia,

disorders,

 

increase in

 

system

+febrile

+granulocytopeni

aplastic

 

serum IgM

 

disorders

neutropenia,

a

anaemia,

 

levels3

 

 

+thrombocyt

 

haemolytic

 

 

 

 

openia

 

anaemia,

 

 

 

 

 

 

lymphadenopa

 

 

 

 

 

 

thy

 

 

 

Immune

infusion

hypersensitivity

 

anaphylaxis

tumour lysis

infusion-related

system

related

 

 

 

syndrome,

acute reversible

disorders

reactions4,

 

 

 

cytokine

thrombocytopenia

 

angioedema

 

 

 

release

 

 

 

 

 

 

 

 

 

 

syndrome4,

 

 

 

 

 

 

serum

 

 

 

 

 

 

sickness

 

Metabolism

 

hyperglycaemia,

 

 

 

 

and nutrition

 

weight decrease,

 

 

 

 

disorders

 

peripheral

 

 

 

 

 

 

oedema, face

 

 

 

 

 

 

oedema,

 

 

 

 

 

 

increased LDH,

 

 

 

 

 

 

hypocalcaemia

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Psychiatric

 

 

depression,

 

 

 

disorders

 

 

nervousness,

 

 

 

Nervous

 

paraesthesia,

dysgeusia

 

peripheral

cranial

system

 

hypoaesthesia,

 

 

neuropathy,

neuropathy8,

disorders

 

agitation,

 

 

facial nerve

loss of other

 

 

insomnia,

 

 

palsy5

senses5

 

 

vasodilatation,

 

 

 

 

 

 

dizziness, anxiety

 

 

 

 

Eye disorders

 

lacrimation

 

 

severe vision

 

 

 

disorder,

 

 

loss5

 

 

 

conjunctivitis

 

 

 

 

Ear and

 

tinnitus, ear pain

 

 

 

hearing loss5

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

+myocardial

+left

severe cardiac

heart failure4

 

disorders

 

infarction4 and 6,

ventricular

disoders 4 and 6

and 6

 

 

 

arrhythmia,

failure,

 

 

 

 

 

+atrial

+supraventricu

 

 

 

 

 

fibrillation,

lar

 

 

 

 

 

tachycardia,

tachycardia,

 

 

 

 

 

+cardiac disorder

+ventricular

 

 

 

 

 

 

tachycardia,

 

 

 

 

 

 

+angina,

 

 

 

 

 

 

+myocardial

 

 

 

 

 

 

ischaemia,

 

 

 

 

 

 

bradycardia

 

 

 

Vascular

 

hypertension,

 

 

vasculitis

 

disorders

 

orthostatic

 

 

(predominatel

 

 

 

hypotension,

 

 

y cutaneous),

 

 

 

hypotension

 

 

leukocytoclast

 

 

 

 

 

 

ic vasculiti

 

Respiratory,

 

Bronchospasm4,

asthma,

interstitial

respiratory

lung infiltration

thoracic and

 

respiratory

bronchiolitis

lung disease7

failure4

 

mediastinal

 

disease, chest

obliterans,

 

 

 

disorders

 

pain, dyspnoea,

lung disorder,

 

 

 

 

 

increased cough,

hypoxia

 

 

 

 

 

rhinitis

 

 

 

 

Gastrointestin

nausea

vomiting ,

abdominal

 

gastro-intestin

 

al disorders

 

diarrhoea,

enlargement

 

al perforation7

 

 

 

abdominal pain,

 

 

 

 

 

 

dysphagia,

 

 

 

 

 

 

stomatitis,

 

 

 

 

 

 

constipation,

 

 

 

 

 

 

dyspepsia,

 

 

 

 

 

 

anorexia, throat

 

 

 

 

 

 

irritation

 

 

 

 

Skin and

pruritus,

urticaria,

 

 

severe bullous

 

subcutaneous

rash,

sweating, night

 

 

skin reactions,

 

tissue

+alopecia

sweats, +skin

 

 

Stevens-Johns

 

disorders

 

disorder

 

 

on Syndrome

 

 

 

 

 

 

toxic

 

 

 

 

 

 

epidermal

 

 

 

 

 

 

necrolysis

 

 

 

 

 

 

(Lyell’s

 

 

 

 

 

 

Syndrome) 7,

 

Musculoskelet

 

hypertonia,

 

 

 

 

al, connective

 

myalgia,

 

 

 

 

tissue and

 

arthralgia, back

 

 

 

 

bone disorders

 

pain, neck pain,

 

 

 

 

 

 

pain

 

 

 

 

Renal and

 

 

 

 

renal failure4

 

urinary

 

 

 

 

 

 

disorders

 

 

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

General

fever , chills,

tumour pain,

infusion site

 

 

 

disorders and

asthenia,

flushing, malaise,

pain

 

 

 

administration

headache

cold syndrome,

 

 

 

 

site conditions

 

+fatigue,

 

 

 

 

 

 

+shivering,

 

 

 

 

 

 

+multi-organ

 

 

 

 

 

 

failure4

 

 

 

 

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 infusionrelated 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 IRRs

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.

Signs and symptoms suggestive of an IRR were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe IRRs (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is <1% of patients by the eighth cycle of MabThera-containing treatment.

Description of selected adverse reactions

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.

Localized 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% 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 haematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation,

have been reported, the majority of which were in patients receiving 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 MabThera-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. During the treatment course 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. Studies in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1x109/L between day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to day 42) following treatment with MabThera plus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of 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 adverse 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 ischaemia) 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 infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).

Respiratory system

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

Neurologic disorders

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

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

Gastrointestinal disorders

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of non-Hodgkgin 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).

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

Skin and subcutaneous tissue disorders:

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

Patient subpopulations - 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

Elderly patients ( 65 years)

The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (<65 years), with previously untreated or relapsed/refractory CLL.

Experience from rheumatoid arthritis

Summary of the safety profile

The overall safety profile of 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 moderate to 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.

Tabulated list of adverse reactions

Adverse reactions are listed in Table 2. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most frequent adverse reactions considered due to receipt of MabThera IRRs. The overall incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during the initial course. In addition to adverse reactions seen in RA clinical trials for MabThera, 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

Very Common

Common

Uncommon

Rare

Very rare

Class

 

 

 

 

 

 

 

 

Infections and

upper respiratory

Bronchitis, sinusitis,

 

 

PML,

infestations

tract infection,

gastroenteritis, tinea

 

 

reactivation of

 

urinary tract

pedis

 

 

hepatitis B

 

infections

 

 

 

 

Blood and

 

neutropenia1

 

late neutropenia2

Serum

lymphatic

 

 

 

 

sickness-like

system

 

 

 

 

reaction

disorders

 

 

 

 

 

Cardiac

 

 

 

Angina pectoris,

Atrial flutter

disorders

 

 

 

atrial fibrillation,

 

 

 

 

 

heart failure,

 

 

 

 

 

myocardial

 

 

 

 

 

infarction

 

Immune system

3Infusion related

 

3Infusion related

 

 

disorders

reactions

 

reactions

 

 

General

(hypertension,

 

(generalized

 

 

disorders and

nausea, rash,

 

oedema,

 

 

administration

pyrexia, pruritus,

 

bronchospasm,

 

 

site conditions

urticaria, throat

 

wheezing,

 

 

 

irritation, hot

 

laryngeal

 

 

 

flush, hypotension,

 

oedema,

 

 

 

rhinitis, rigors,

 

angioneurotic

 

 

 

tachycardia,

 

oedema,

 

 

 

fatigue,

 

generalized

 

 

 

oropharyngeal

 

pruritis,

 

 

 

pain, peripheral

 

anaphylaxis,

 

 

 

oedema, erythma)

 

anaphylactoid

 

 

 

 

 

reaction)

 

 

Metabolism

 

hypercholesterolemia

 

 

 

and nutritional

 

 

 

 

 

disorders

 

 

 

 

 

Nervous system

headache

paraesthesia,

 

 

 

disorders

 

migraine, dizziness,

 

 

 

 

 

sciatica

 

 

 

Skin and

 

alopecia

 

 

Toxic Epidermal

subcutaneous

 

 

 

 

Necrolysis

tissue disorders

 

 

 

 

(Lyell’s

 

 

 

 

 

Syndrome),

 

 

 

 

 

Stevens-Johnson

 

 

 

 

 

Syndrome5

Psychiatric

 

depression, anxiety

 

 

 

disorders

 

 

 

 

 

Gastrointestinal

 

dyspepsia, diarrhoea,

 

 

 

disorders

 

gastro-oesophageal

 

 

 

 

 

reflux, mouth

 

 

 

 

 

ulceration, upper

 

 

 

 

 

abdominal pain

 

 

 

Musculo

 

arthralgia /

 

 

 

skeletal

 

musculoskeletal

 

 

 

disorders

 

pain, osteoarthritis,

 

 

 

 

 

bursitis

 

 

 

Investigations

decreased IgM

decreased IgG

 

 

 

 

levels4

levels4

 

 

 

1 Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials 2 Frequency category derived from post-marketing data.

3 Reactions occurring during or within 24 hours of infusion. See also infusionrelated reactions below. IRRs may occur as a result of hypersensitivity and/or to the mechanism of action.

4 Includes observations collected as part of routine laboratory monitoring. 5 Includes fatal cases

Multiple courses

Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs following first MabThera exposure was highest during the first 6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the first treatment course), RA exacerbation and infections all of which were more frequent in the first 6 months of treatment.

Infusion-related reactions

The most frequent ADRs following receipt of MabThera in clinical studies were 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 declined with subsequent infusions. In clinical trials fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events, and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Severe IRRs with fatal outcome have been reported in the post-marketing setting.

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

Description of selected adverse reactions

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 antibiotics, 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.

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

Cardiovascular adverse reactions

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

Neurologic events

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

Neutropenia

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

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

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported in the post-marketing setting, some of which were associated with fatal infections.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal outcome, have been reported very rarely.

Laboratory abnormalities

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

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

Experience from granulomatosis with polyangiitis and microscopic polyangiitis

In the clinical trial in granulomatosis with polyangiitis and microscopic polyangitis, 99 patients were treated with MabThera (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1).

Tabulated list of adverse reactions

The ADRs listed in Table 3 were all adverse events which occurred at an incidence of ≥ 5% in the MabThera group.

Table 3 Adverse drug reactions occurring at 6-months in ≥ 5% of patients receiving MabThera, and at a higher frequency than the comparator group, in the pivotal clinical study.

Body System

Rituximab

Adverse event

(n=99)

Blood and lymphatic

 

system disorders

 

Thrombocytopenia

7%

Gastrointestinal

 

disorders

 

Diarrhoea

18%

Dyspepsia

6%

Constipation

5%

General disorders and

 

administration site conditions

 

Peripheral oedema

16%

Immune system disorders

 

Cytokine release syndrome

5%

Body System

Rituximab

Adverse event

(n=99)

Infections and infestations

 

Urinary tract infection

7%

Bronchitis

5%

Herpes zoster

5%

Nasopharyngitis

5%

Investigations

 

Decreased haemoglobin

6%

Metabolism and nutrition disorders

 

Hyperkalaemia

5%

Musculoskeletal and connective

 

tissue disorders

 

Muscle spasms

18%

Arthralgia

15%

Back pain

10%

Muscle weakness

5%

Musculoskeletal pain

5%

Pain in extremities

5%

Nervous system disorders

 

Dizziness

10%

Tremor

10%

Psychiatric disorders

 

Insomnia

14%

Respiratory, thoracic and

 

mediastinal disorders

 

Cough

12%

Dyspnoea

11%

Epistaxis

11%

Nasal congestion

6%

Skin and subcutaneous

 

tissue disorders

 

Acne

7%

Vascular disorders

 

Hypertension

12%

Flushing

5%

Selected adverse drug reactions

Infusion related reactions:

IRRs in the GPA and MPA clinical trial were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators in the safety population. Ninety nine patients were treated with MabThera and 12% experienced at least one IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing, throat irritation, and tremor. MabThera was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.

Infections

In the 99 MabThera patients, the overall rate of infection was approximately 237 per 100 patient years (95% CI 197 - 285) at the 6-month primary endpoint. Infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections.

The rate of serious infections was approximately 25 per 100 patient years. The most frequently reported serious infection in the MabThera group was pneumonia at a frequency of 4%.

Malignancies

The incidence of malignancy in MabThera treated patients in the granulomatosis with polyangiitis and microscopic polyangiitis clinical trial was 2.00 per 100 patient years at the trial common closing date (when the final patient had completed the follow-up period). On the basis of standardized incidence ratios, the incidence of malignancies appears to be similar to that previously reported in patients with ANCA-associated vasculitis.

Cardiovascular adverse reactions

Cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149-470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI 3 -15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see Section 4.4).

Neurologic events

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

Hepatitis-B reactivation

A small number of cases of hepatitis-B reactivation, some with fatal outcome, have been reported in granulomatosis with polyangiitis and microscopic polyangiitis patients receiving MabThera in the postmarketing setting.

Hypogammaglobulinaemia

Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in granulomatosis with polyangiitis and microscopic polyangiitis patients treated with MabThera. At 6 months, in the active-controlled, randomised, double-blind, multicenter, non-inferiority trial, in the MabThera group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the cyclophosphamide group. There was no increased rate in overall infections or serious infections in patients with low IgA, IgG or IgM.

Neutropenia

In the active-controlled, randomised, double-blind, multicenter, non-inferiority trial of MabThera in granulomatosis with polyangiitis and microscopic polyangiitis, 24% of patients in the MabThera group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in MabThera-treated patients. The effect of multiple MabThera courses on the development of neutropenia in granulomatosis with polyangiitis and microscopic polyangiitis patients has not been studied in clinical trials.

Skin and subcutaneous tissue disorders:

Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal outcome, have been reported very rarely.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

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

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

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on 95 % of all B cell non-Hodgkin’s lymphomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon

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

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fc receptors on the surface of granulocytes, macrophages and NK cells. Rituximab binding to 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 haematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg 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. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of MabThera. In patients with granulomatosis with polyangiitis or microscopic polyangiitis, the number of peripheral blood B cells decreased to <10 cells/μL after two weekly infusions of rituximab 375 mg/m2, and remained at that level in most patients up to the 6 month timepoint. The majority of patients (81%) showed signs of B cell return, with counts >10 cells/μL by month 12, increasing to 87% of patients by month 18.

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

Follicular lymphoma

Monotherapy

Initial treatment, weekly for 4 doses

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL received 375 mg/m2 of MabThera as an intravenous infusion once weekly for four weeks. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI95 % 41% - 56%) with a 6% complete response (CR) and a 42% partial response (PR) rate. The projected median time to progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58% vs. 12%), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT. Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) on response to 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 trial, 37 patients with relapsed or chemoresistant, low grade or follicular B cell NHL received 375 mg/m2 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 trials, 39 patients with relapsed or chemoresistant, bulky disease (single lesion 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m2 of MabThera as intravenous infusion weekly for four doses. The ORR was 36 % (CI95 % 21 % – 51 %; CR 3 %, PR 33 %) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

Re-treatment, weekly for 4 doses

In a multi-centre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular B cell NHL, who had achieved an objective clinical response to a prior course of MabThera, were re-treated with 375 mg/m2 of MabThera as intravenous infusion weekly for four doses. Three of the patients had received two courses of MabThera before enrolment and thus were given a third course in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORR was 38% (CI95 % 26% – 51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months (range 5.4 – 26.6). This compares favourably with the TTP achieved after the prior course of 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/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1 -5) every 3 weeks for 8 cycles or 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 was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to

treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p< 0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively

(p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test).

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

Results from three other randomised trials using 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 4.

Table 4 Summary of key results from four phase III randomised studies evaluating the benefit of MabThera with different chemotherapy regimens in follicular lymphoma

 

Treatment,

Median

 

CR,

Median

OS

Study

FU,

ORR, %

TTF/PFS/ EFS

rates,

N

%

 

months

 

mo

%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Median TTP:

53-months

M39021

CVP, 159

14.7

71.1

R-CVP, 162

33.6

80.9

 

 

 

 

 

P<0.0001

p=0.029

 

 

 

 

 

 

 

 

 

 

 

 

Median TTF: 2.6

18-months

GLSG’00

CHOP, 205

years

R-CHOP, 223

Not reached

 

 

 

 

 

 

 

p < 0.001

p = 0.016

 

 

 

 

 

 

 

 

 

 

 

 

Median PFS: 28.8

48-months

 

MCP, 96

 

OSHO 39

Not reached

 

 

 

-

R-MCP, 105

 

p < 0.0001

 

p = 0.0096

 

CHVP-IFN,

 

 

 

Median EFS: 36

42-months

 

 

FL2000

Not reached

R-CHVP-IFN,

 

 

p < 0.0001

 

 

 

 

p = 0.029

 

 

 

 

 

 

 

 

 

 

 

 

EFS – Event Free Survival

TTP – Time to progression or death

PFS – Progression-Free Survival

TTF – Time to Treatment Failure

OS rates – survival rates at the time of the analyses

Maintenance therapy

Previously untreated follicular lymphoma

In a prospective, open label, international, multi-centre, phase III trial 1193 patients with previously untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP (n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1078 patients responded to induction therapy, of which 1018 were randomised to 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.

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 observation in patients with previously untreated follicular lymphoma (Table 5).

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 5). The results of the primary analysis were confirmed with longer follow-up (median observation time: 48 months and 73 months), and have been added to Table 5 to show the comparison between the 25 and 48 and 73 month follow up periods.

Table 5 Maintenance phase: overview of efficacy results MabThera vs. observation after 73 months median observation time (compared with results of primary analysis based on 25 months median observation time, and updated analysis based on 48 months median observation time)

 

Observation

MabThera

Log-rank P

Risk reduction

 

N=513

N=505

value

 

 

 

 

 

Primary efficacy

 

 

 

 

PFS (median)

48.5 months

NR

<0.0001

42%

 

[48.4 months]

[NR]

[<0.0001]

[45%]

 

(NR)

(NR)

(<0.0001)

(50%)

Secondary efficacy

 

 

 

 

EFS (median)

48.4 months

NR

<0.0001

39%

 

[47.6 months]

[NR]

[< 0.0001]

[42%]

 

(37.8 months)

(NR)

(< 0.0001)

(46%)

OS (median)

NR

NR

0.8959

2%

 

[NR]

[NR]

[0.9298]

[ 2%]

 

(NR)

(NR)

(0.7246)

(11%)

TNLT (median)

71.0 months

NR

<0.0001

37%

 

[60.2 months]

[NR]

[<0.0001]

[39%]

 

(NR)

(NR)

(0.0003)

(39%)

TNCT (median)

85.1 months

NR

0.0006

30%

 

[NR]

[NR]

[0.0006]

[34%]

 

(NR)

(NR)

(0.0011)

(40%)

ORR*

60.7%

79.0%

<0.0001#

OR=2.43

 

[60.7%]

[79.0%]

[<0.0001#]

[OR=2.43]

 

(55.0%)

(74.0%)

(< 0.0001)

(OR =2.33)

Complete Response

52.7%

66.8%

<0.0001

OR=2.34

(CR/CRu) rate*

[52.7%]

[72.2%]

[<0.0001]

[OR=2.34]

 

(47.7%)

(66.8%)

(< 0.0001)

[ (OR = 2.21)

*At end of maintenance/observation; # p values from chi-squared test

Main values correspond to 73 months median observation time, italicized values in brackets correspond to 48 months median observation time, and values in parentheses correspond to 25 months median observation time (primary analysis). 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, OR: odds ratio.

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/m2 body surface area given every 3 months until disease progression or for a maximum period of two years.

The final efficacy analysis included all patients randomised to both parts of the study. After a median observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to CHOP (see Table 6).

Table 6 Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months median observation time)

 

CHOP

R CHOP

p value

Risk Reduction1)

Primary efficacy

 

 

 

 

ORR2)

74 %

87 %

0.0003

Na

CR2)

16 %

29 %

0.0005

Na

PR2)

58 %

58 %

0.9449

Na

1)Estimates were calculated by hazard ratios

2)Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of CR versus PR versus non-response (p < 0.0001)

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

For patients randomised to the maintenance phase of the trial, the median observation time was 28 months from maintenance randomisation. Maintenance treatment with 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 7 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 %

 

 

 

 

 

Subgroup analysis

 

 

 

 

PFS

11.6

37.5

< 0.0001

71 %

CHOP

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

NR

NR

0.0348

55 %

CHOP

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 of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (table 7). 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 overall survival for both patients responding to CHOP and patients responding to R-CHOP, although longer follow-up is required to confirm this observation.

Diffuse large B cell non-Hodgkin’s lymphoma

In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years) with diffuse large B cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1-5) every 3 weeks for eight cycles, or 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 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 randomised trials, a total of 817 previously untreated patients and 552 patients with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or MabThera in combination with FC (R-FC). MabThera was administered at a dosage of 375 mg/m2 during the first cycle one day prior to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had previously been treated with monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 8a and Table 8b) and 552 patients (276 R-FC, 276 FC) for the relapsed/refractory study (Table 9) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p = 0.0319, log-rank test) (Table 8a). The benefit in terms of PFS was consistently observed in most patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 8b).

Table 8a First-line treatment of chronic lymphocytic leukaemia

Overview of efficacy results for MabThera plus FC vs. FC alone - 48.1 months median observation time

Efficacy Parameter

Kaplan-Meier Estimate of

Risk

 

Median Time to Event (Months)

Reduction

 

FC

R-FC

Log-Rank

 

 

(N = 409)

(N=408)

p value

 

Progression free survival (PFS)

32.8

55.3

<0.0001

45%

Overall survival

NR

NR

0.0319

27%

Event free survival

31.3

51.8

<0.0001

44%

Response rate (CR, nPR, or PR)

72.6%

85.8%

<0.0001

n.a.

CR rates

16.9%

36.0%

<0.0001

n.a.

 

 

 

 

 

Duration of response*

36.2

57.3

<0.0001

44%

Disease free survival (DFS)**

48.9

60.3

0.0520

31%

Time to new treatment

47.2

69.7

<0.0001

42%

 

 

 

 

 

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

**: only applicable to patients achieving a CR

Table 8b First-line treatment of chronic lymphocytic leukaemia

Hazard ratios of progression-free survival according to Binet stage (ITT) – 48.1 months median observation time

Progression free survival (PFS)

Number of

Hazard Ratio

p-value (Wald

 

patients

(95% CI)

test, not

 

FC

R FC

 

adjusted)

Binet stage A

0.39 (0.15; 0.98)

0.0442

Binet stage B

0.52 (0.41; 0.66)

<0.0001

Binet stage C

0.68 (0.49; 0.95)

0.0224

 

 

 

 

 

CI: Confidence Interval

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

Table 9 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

Risk

 

Median Time to Event (Months)

Reduction

 

FC

R-FC

Log-Rank

 

 

(N = 276)

(N=276)

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.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with MabThera in all subsets of the paediatric population with follicular lymphoma and chronic lymphocytic leukaemia. See Section 4.2 for information on paediatric use.

Clinical experience in rheumatoid arthritis

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

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one or more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to the criteria of the American College of Rheumatology (ACR). 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 MabThera between weeks 24 and 56, under an open label extension study protocol.

Studies of MabThera 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 MabThera treatment are insufficient, in particular concerning the risk of development of malignancies and PML.

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 10). 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 10 Clinical response outcomes at primary endpoint in Trial 1 (ITT population)

 

Outcome†

Placebo+MTX

MabThera+MTX

 

 

 

 

(2 x 1000 mg)

Trial 1

 

N= 201

N= 298

 

 

 

 

 

 

ACR20

(18%)

153 (51%)***

 

ACR50

11 (5%)

80 (27%)***

 

ACR70

(1%)

37 (12%)***

 

EULAR Response

(22%)

193 (65%)***

 

(Good/Moderate)

 

 

 

 

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, in all studies 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 10).

Radiographic response

Structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.

In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitor therapies, receiving 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 MabThera 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 11).

Table 11 Radiographic outcomes at 1 year (mITT population)

 

Placebo+MTX

MabThera +MTX

 

 

2 × 1000 mg

 

 

 

Trial 1

(n = 184)

(n = 273)

Mean change from baseline:

 

 

Modified total sharp score

2.30

1.01*

 

 

 

Erosion score

1.32

0.60*

 

 

 

Joint space narrowing score

0.98

0.41**

 

 

 

Proportion of patients with no

46%

53%, NS

radiographic change

 

 

Proportion of patients with no erosive

52%

60%, NS

change

 

 

150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX by one year * p <0.05, ** p < 0.001. Abbreviation: NS, non siginficant

Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis at 2 years in Trial 1 demonstrated significantly reduced progression of structural joint damage in patients receiving 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) were observed in patients treated with MabThera compared to patients treated with methotrexate alone. The proportions of MabThera 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 12).

Significant improvement in health related quality of life was also demonstrated with significant improvement in both the physical health score (PHS) and mental health score (MHS) of the SF-36. Further, significantly higher proportion of patients achieved MCIDs for these scores (Table 12).

Table 12 Physical Function and Quality of Life outcomes at week 24 in Trial 1

Outcome†

 

Placebo+MTX

MabThera+MTX

 

 

 

(2 x 1000 mg)

 

 

n=201

n=298

Mean change in HAQ DI

0.1

 

0.4***

% HAQ DI MCID

-

20%

-

51%

Mean change in FACIT T

0.5

 

9.1

***

 

 

-

 

n=197

n=294

 

 

 

 

**

Mean change in SF 36 PHS

0.9

5.8***

% SF 36 PHS MCID

 

13%

48%***

Mean change in SF 36 MHS

1.3

 

4.7

 

% SF 36 MHS MCID

 

20%

38%*

† Outcome at 24 weeks

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

Efficacy in autoantibody (RF and or anti-CCP) seropositive patients

Patients seropositive to Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide (anti-CCP) who were treated with 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 13). 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 13 Summary of efficacy by baseline autoantibody status

 

Week 24

Week 48

 

Seropositive

Seronegative

Seropositive

Seronegative

 

(n=514)

(n=106)

(n=506)

(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.

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)

 

 

 

 

patients

ACR50

 

ACR20

 

 

 

of

ACR70

%

 

 

 

 

 

 

 

 

1st

2nd

3rd

4th

Course

Course

Course

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.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with MabThera in all subsets of the paediatric population with autoimmune arthritis. See Section 4.2 for information on paediatric use.

Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis

A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis (75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator, randomised, double-blind, multicenter, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2mg/kg/day) for 3-6 months or MabThera (375 mg/m2) once weekly for 4 weeks. All patients in the cyclophosphamide arm received azathioprine maintenance therapy in during follow-up. Patients in both arms received 1000mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day). Prednisone tapering was to be completed by 6 months from the start of study treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%. The trial demonstrated non-inferiority of MabThera to cyclophosphamide for complete remission (CR) at 6 months (Table 14).

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing disease (Table 15).

Table 14 Percentage of patients who achieved complete remission at 6 months (Intent-to-treat population*)

 

 

 

 

 

MabThera

Cyclophosphamide

 

Treatment Difference

 

 

 

 

 

(n 99)

 

(n 98)

 

 

(MabThera-

 

 

 

 

 

 

 

 

 

 

Cyclophosphamide)

 

 

 

 

 

 

 

 

 

 

 

 

Rate

 

 

63.6%

53.1%

 

10.6%

 

 

 

 

 

 

 

 

 

 

95.1%b CI

 

 

 

 

 

 

 

 

 

 

( 3.2%, 24.3%) a

 

 

 

 

 

 

 

 

 

 

 

 

CI = confidence interval.

 

 

 

 

 

 

 

* Worst case imputation

lower bound ( 3.2%) was higher than the pre-determined

 

a Non-inferiority was

demonstrated since the

 

non-inferiority margin ( 20%).

 

 

 

 

 

 

b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.

Table 15 Complete remission at 6-months by disease status

 

 

 

 

 

 

 

MabThera

 

Cyclophosphamide

 

Difference (CI 95%)

 

All patients

 

n=99

 

n=98

 

 

 

Newly diagnosed

 

n=48

 

n=48

 

 

 

Relapsing

 

n=51

 

n=50

 

 

 

Complete remission

 

 

 

 

 

 

All Patients

 

63.6%

 

53.1%

 

 

10.6% ( 3.2, 24.3)

 

Newly diagnosed

 

60.4%

 

64.6%

 

 

− 4.2% (− 23.6, 15.3)

 

Relapsing

 

66.7%

 

42.0%

 

 

24.7% (5.8, 43.6)

Worst case imputation is applied for patients with missing data

Complete remission at 12 and 18 months

In the MabThera group, 48% of patients achieved CR at 12 months, and 39% of patients achieved CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the MabThera group compared with four in the cyclophosphamide group.

Retreatment with MabThera

Based upon investigator judgment, 15 patients received a second course of MabThera therapy for treatment of relapse of disease activity which occurred between 6 and 18 months after the first course of MabThera. The limited data from the present trial preclude any conclusions regarding the efficacy of subsequent courses of MabThera in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses (i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with MabThera has been achieved, continued immunosuppressive therapy may be considered to prevent relapse. The efficacy and safety of MabThera in maintenance therapy has not been established.

Laboratory evaluations

A total of 23/99 (23%) MabThera-treated patients in the trial tested positive for HACA by 18 months. None of the 99 MabThera-treated patients were HACA positive at screening. The clinical relevance of HACA formation in MabThera-treated patients is unclear.

5.2 Pharmacokinetic properties

Non-Hodgkin’s lymphoma

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

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

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

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

Chronic lymphocytic leukaemia

MabThera was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to 500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL patients. The mean Cmax (N=15) was 408 µg/mL (range, 97 – 764 µg/mL) after the fifth 500 mg/ m2 infusion and the mean terminal half-life was 32 days (range, 14 – 62 days).

Rheumatoid arthritis

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

The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first infusion ranged from 157 to 171 g/mL for 2 x 500 mg dose and ranged from 298 to 341 g/mL for 2 x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 g/mL for the

2 500 mg dose and ranged from 355 to 404 g/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 Cmax was 16 to 19% higher following second infusion compared to the first infusion for both doses.

The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was

170 to 175 g/mL for 2 x 500 mg dose and 317 to 370 g/mL for 2 x 1000 mg dose. Cmax following second infusion, was 207 g/mL for the 2 x 500 mg dose and ranged from 377 to 386 g/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 g/mL and a mean terminal half-life of 19.2 days.

Granulomatosis with polyangiitis and microscopic polyangiitis

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

5.3 Preclinical safety data

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

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to

100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the foetuses was observed, which persisted 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 immunisation.

Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant for this molecule. No long-term animal studies have been performed to establish the carcinogenic potential of rituximab. Specific studies to determine the effects of rituximab on fertility have not been performed. In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or females were observed.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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

Unopened vial 30 months

Diluted product

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 after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal and other handling

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 discolouration prior to administration.

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

7. MARKETING AUTHORISATION HOLDER

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/067/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 2 June 1998

Date of latest renewal: 2 June 2008

10. DATE OF REVISION OF THE TEXT

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

1. NAME OF THE MEDICINAL PRODUCT

MabThera 1400 mg solution for subcutaneous injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 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 the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear to opalescent, colourless to yellowish liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 follicular lymphoma in combination with chemotherapy.

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

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.

4.2 Posology and method of administration

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

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

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

Posology

The recommended dose of MabThera subcutaneous formulation used for adult patients is a subcutaneous 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 full dose 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 full intravenous dose is successfully administered.

Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent 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 given via subcutaneous injection only. The 1400 mg strength is intended for subcutaneous use in non Hodgkin lymphoma (NHL) only.

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: 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 8cycles.

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

Maintenance therapy

Previously untreated follicular lymphoma

The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment for patients 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 disease progression or for a maximum period of two years.

Relapsed/refractory follicular lymphoma

The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment for patients 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 disease progression or for a maximum period of two years.

Diffuse large B cell non-Hodgkin's lymphoma

MabThera should be used in combination with CHOP chemotherapy. The recommended dose is: first cycle, 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. In total: 8 cycles.

MabThera is administered on day 1 of each chemotherapy cycle 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.

Dose 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 (see section 4.8).

Special populations

Paediatric population

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

Elderly

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

Method of administration

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 syringe immediately prior to administration to avoid potential needle clogging.

MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall and never 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 should be restricted to the abdominal wall.

During the treatment course with MabThera subcutaneous formulation, other medicinal products for subcutaneous 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, if appropriate.

Intravenous infusion administration:

The Summary of Product Characteristics (SmPC) of MabThera100 mg and 500 mg concentrate for solution for infusion should be referred to for information on dosing instructions and method of administration.

4.3 Contraindications

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

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

4.4 Special warnings and precautions for use

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

The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation in the approved indications Treatment of non Hodgkin lymphoma (strength 1400 mg) and Treatment of

Chronic 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 follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy cannot be recommended as the safety of the once weekly subcutaneous administration has not been established.

Progressive multifocal leukoencephalopathy

Use of MabThera may be associated with an increased risk of progressive multifocal leukoencephalopathy (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, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

If a patient develops PML, the dosing of 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.

Infusion/Administration-related reactions

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

This set of reactions which includes syndrome of cytokine release, tumor lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the 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 of the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first MabThera intravenous infusion. They were characterized by pulmonary events and in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

Severe cytokine release syndrome is characterised by severe 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.

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 with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 109/L.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of 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 administration, consideration should be given to withholding 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 hypotension and bronchospasm in 10 % of patients) see section 4.8. These symptoms are usually reversible with interruption of 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.

Administration related reactions have been observed in up to 50% of patients treated with MabThera subcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the subcutaneous injection 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 (see section 4.8).

Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical trials. Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see section 4.8). Some local cutaneous reactions occurred more than 24 hours after the MabThera subcutaneous 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 full dose of MabThera by intravenous infusion, using MabThera intravenous formulation. The highest risk of experiencing an administration related reaction is generally observed at cycle one. Beginning the therapy with MabThera intravenous infusion would allow a better handling of the administration reactions by slowing 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 full

intravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

As with the intravenous formulation, MabThera subcutaneous formulation should be administered in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced healthcare professional. Premedication consisting of an analgesic/antipyretic and an antihistamine 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. A longer 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 are suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinal product administration.

Cardiac disorders

Angina pectoris, 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 109/L and/or platelet counts < 75 x 109/L as clinical experience in this population is limited. The MabThera intravenous formulation 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 patients receiving the MabThera intravenous formulation including fulminant hepatitis with fatal outcome. The majority of these patients were also exposed to cytotoxic chemotherapy. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. At minimum this should include HBsAg-status and HBcAb-status.These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with MabThera. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

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

Immunisation

The safety of immunisation with live viral vaccines, following MabThera therapy has not been studied for 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 be reduced. In a non-randomized study, patients with relapsed low-grade NHL who received the MabThera intravenous formulation as 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).

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

Skin reactions

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

4.5 Interaction with other medicinal products and other forms of interaction

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 fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of MabThera.

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.

4.6 Fertility, pregnancy and lactation

Contraception in males and females

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

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 MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3).For these reasons MabThera should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Breast-feeding

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with MabThera and for 12 months following MabThera treatment.

Fertility

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

4.7 Effects on ability to drive and use machines

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 MabThera would have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

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 MabThera intravenous formulation.

Summary of the safety profile

During the development programme, the safety profile of MabThera subcutaneous formulation was comparable to that of the intravenous formulation with the exception of local cutaneous reactions. Local cutaneous reactions, including injection site reactions were very common in patients receiving MabThera subcutaneous formulation. In the phase 3 SABRINA trial (BO22334), local cutaneous reaction were reported in up to 20% of patients receiving subcutaneous MabThera. The most common local cutaneous reactions in the Mabthera subcutaneous arm were injection erythema (13%), injection pain (7%) and injection site oedema (4%).Events seen following subcutaneous administration were mild or 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). Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections.

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 during induction and maintenance (SABRINA/BO22334) and during maintenance only (SparkThera/BP22333). InSABRINA, severe administration-related reactions (grade≥3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation. These events were Grade 3 injection site rash and dry mouth. InSparkThera, 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 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 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 disorders, 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 Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common ( 1/100 to

< 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

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

Tabulated list of adverse reactions

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

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Infections and

bacterial

sepsis,

 

serious viral

 

 

infestations

infections,

+pneumonia,

 

infection2

 

 

 

viral

+febrile infection,

 

 

 

 

 

infections,

+herpes zoster,

 

 

 

 

 

+bronchitis

+respiratory tract

 

 

 

 

 

 

infection, fungal

 

 

 

 

 

 

infections,

 

 

 

 

 

 

infections of

 

 

 

 

 

 

unknown

 

 

 

 

 

 

aetiology, +acute

 

 

 

 

 

 

bronchitis,

 

 

 

 

 

 

+sinusitis,

 

 

 

 

 

 

hepatitis B1

 

 

 

 

Blood and

neutropenia,

anaemia,

coagulation

 

transient

late neutropenia3

lymphatic

leucopenia,

+pancytopenia,

disorders,

 

increase in

 

system

+febrile

+granulocytopeni

aplastic

 

serum IgM

 

disorders

neutropenia,

a

anaemia,

 

levels3

 

 

+thrombocyt

 

haemolytic

 

 

 

 

openia

 

anaemia,

 

 

 

 

 

 

lymphadenopa

 

 

 

 

 

 

thy

 

 

 

Immune

infusion

hypersensitivity

 

anaphylaxis

tumour lysis

infusion-related

system

related

 

 

 

syndrome,

acute reversible

disorders

reactions4,

 

 

 

cytokine

thrombocytopenia

 

angioedema

 

 

 

release

 

 

 

 

 

 

 

 

 

 

syndrome4,

 

 

 

 

 

 

serum

 

 

 

 

 

 

sickness

 

Metabolism

 

hyperglycaemia,

 

 

 

 

and nutrition

 

weight decrease,

 

 

 

 

disorders

 

peripheral

 

 

 

 

 

 

oedema, face

 

 

 

 

 

 

oedema,

 

 

 

 

 

 

increased LDH,

 

 

 

 

 

 

hypocalcaemia

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Psychiatric

 

 

depression,

 

 

 

disorders

 

 

nervousness,

 

 

 

Nervous

 

paraesthesia,

dysgeusia

 

peripheral

cranial

system

 

hypoaesthesia,

 

 

neuropathy,

neuropathy,

disorders

 

agitation,

 

 

facial nerve

loss of other

 

 

insomnia,

 

 

palsy5

senses5

 

 

vasodilatation,

 

 

 

 

 

 

dizziness, anxiety

 

 

 

 

Eye disorders

 

lacrimation

 

 

severe vision

 

 

 

disorder,

 

 

loss5

 

 

 

conjunctivitis

 

 

 

 

Ear and

 

tinnitus, ear pain

 

 

 

hearing loss5

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

+myocardial

+left

severe cardiac

heart failure4

 

disorders

 

infarction4 and 6,

ventricular

disorders 4 and 6

and 6

 

 

 

arrhythmia,

failure,

 

 

 

 

 

+atrial

+supraventricu

 

 

 

 

 

fibrillation,

lar

 

 

 

 

 

tachycardia,

tachycardia,

 

 

 

 

 

+cardiac disorder

+ventricular

 

 

 

 

 

 

tachycardia,

 

 

 

 

 

 

+angina,

 

 

 

 

 

 

+myocardial

 

 

 

 

 

 

ischaemia,

 

 

 

 

 

 

bradycardia

 

 

 

Vascular

 

hypertension,

 

 

vasculitis

 

disorders

 

orthostatic

 

 

(predominatel

 

 

 

hypotension,

 

 

y cutaneous),

 

 

 

hypotension

 

 

leukocytoclast

 

 

 

 

 

 

ic vasculitis

 

Respiratory,

 

Bronchospasm4,

asthma,

interstitial

respiratory

lung infiltration,

thoracic and

 

respiratory

bronchiolitis

lung disease7

failure4,

 

mediastinal

 

disease, chest

obliterans,

 

 

 

disorders

 

pain, dyspnoea,

lung disorder,

 

 

 

 

 

increased cough,

hypoxia

 

 

 

 

 

rhinitis

 

 

 

 

Gastrointestin

nausea

vomiting ,

abdominal

 

gastro-intestin

 

al disorders

 

diarrhoea,

enlargement

 

al perforation7

 

 

 

abdominal pain,

 

 

 

 

 

 

dysphagia,

 

 

 

 

 

 

stomatitis,

 

 

 

 

 

 

constipation,

 

 

 

 

 

 

dyspepsia,

 

 

 

 

 

 

anorexia, throat

 

 

 

 

 

 

irritation

 

 

 

 

Skin and

pruritis, rash,

urticaria,

 

 

severe bullous

 

subcutaneous

+alopecia

sweating, night

 

 

skin reactions,

 

tissue

 

sweats, +skin

 

 

Stevens-Johns

 

disorders

 

disorder

 

 

on Syndrome

 

 

 

 

 

 

toxic

 

 

 

 

 

 

epidermal

 

 

 

 

 

 

necrolysis

 

 

 

 

 

 

(Lyell’s

 

 

 

 

 

 

Syndrome) 7

 

Musculoskelet

 

hypertonia,

 

 

 

 

al, connective

 

myalgia,

 

 

 

 

tissue and

 

arthralgia, back

 

 

 

 

bone disorders

 

pain, neck pain,

 

 

 

 

 

 

pain

 

 

 

 

Renal and

 

 

 

 

renal failure4

 

urinary

 

 

 

 

 

 

disorders

 

 

 

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

General

fever , chills,

tumour pain,

infusion site

 

 

 

disorders and

asthenia,

flushing, malaise,

pain

 

 

 

administration

headache

cold syndrome,

 

 

 

 

site conditions

 

+fatigue,

 

 

 

 

 

 

+shivering,

 

 

 

 

 

 

+multi-organ

 

 

 

 

 

 

failure4

 

 

 

 

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.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50 % of patients in clinical trials involving MabThera intravenous formulation, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12 % of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent intravenous infusions and is <1% of patients by the eighth cycle of MabThera (containing) treatment.

Description of selected adverse reactions

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.

Localized candida infections as well as Herpes zoster were 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 hematopoietic 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 (PML) and hepatitis C

virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving MabThera in combination with cytotoxic chemotherapy. Progression of Kaposi’s sarcoma has been observed in MabThera-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, 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 of thrombocytopenia was low (<1 %, grade 3/4) and was not different between treatment arms. During the treatment 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. CHOP 88%), 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. 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 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 adverse 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 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.

Respiratory system

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

Neurologic disorders

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

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-Hodgkin’s lymphoma (NHL). 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).

Skin and subcutaneous tissue disorders

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

Patient subpopulations - 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).

Reporting of suspected adverse reactions

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

4.9 Overdose

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

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

Three patients in the MabThera subcutaneous formulation trial SABRINA (BO22334) were inadvertently administered subcutaneous formulation through the intravenous route up to a maximum rituximab 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 no reported adverse event. The two adverse events that were reported were flu-like symptoms, with a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered substances when administered 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 cell non-Hodgkin’s lymphomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon

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

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fc receptors on the surface of granulocytes, macrophages and NK cells. Rituximab binding to 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 recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg 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 of MabThera subcutaneous formulation in Non-Hodgkin’s lymphoma

The clinical experience of MabThera subcutaneous formulation in Non-Hodgkin’s lymphoma is based 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 conducted in patients with previously untreated follicular lymphoma, to investigate the non-inferiority of the pharmacokinetic profile, together with efficacy and safety of MabThera subcutaneous

formulation in combination with CHOP or CVP versus MabThera intravenous formulation in combination with CHOP or CVP.

The objective of the first stage was to establish the rituximab subcutaneous dose that resulted in comparable MabThera subcutaneous formulation serum Ctrough levels compared with MabThera intravenous 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 rituximab compared 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 randomized into the following two treatment groups:

MabThera subcutaneous formulation (n= 205): first cycle MabThera intravenous formulation plus 7 cycles of MabThera subcutaneous formulation in combination 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 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 formulation maintenance therapy once every 8 weeks for 24 months.

MabThera intravenous formulation (n= 205): 8 cycles of MabThera intravenous formulation in

combination 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 therapy once every 8 weeks for 24 months.

The overall response rate point estimates for the pooled analysis of 410 patients in SABRINA stages 1 and 2 are shown in table 2.

Table 2

SABRINA (BO22334) Response Rate Point Estimates (Intent to Treat Population)

 

 

 

 

 

 

 

 

Pooled Stages 1 & 2

 

 

 

 

N = 410

 

 

 

 

 

 

 

 

 

Rituximab

 

Rituximab

 

 

 

intravenous

 

subcutaneous

 

 

 

formulation

 

formulation

 

 

 

 

 

 

 

 

Point estimate

84.4% (173/205)

 

83.4% (171/205)

ORR

 

 

 

 

 

 

95% CI

[78.7%,89.1%]

 

[77.6%,88.2%]

 

 

 

 

 

 

 

 

 

 

 

Point estimate

31.7% (65/205)

 

32.7% (67/205)

CRR

 

 

 

 

 

 

95% CI

[25.4%,38.6%]

 

[26.3%,39.6%]

 

 

 

 

 

 

 

 

 

ORR – Overall Response Rate

CRR – Complete Response Rate

Exploratory analyses showed response rates among BSA, chemotherapy and gender subgroups were not notably different from the ITT population.

Immunogenicity

Data from the development programme of MabThera subcutaneous formulation indicate that the formation of anti-rituximab antibodies (HACAs) after subcutaneous administration is comparable with that observed after intravenous administration. In the SABRINA trial (BO22334) the incidence of treatment-induced/enhanced anti-rituximab antibodies in the subcutaneous group was low and similar to that observed in the intravenous group (2% vs. 1%, respectively). The incidence of treatment-induced/enhanced anti-rHuPH20 antibodies was 6% in the intravenous group compared with 9% in the subcutaneous group, and none of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies. There was no apparent impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety or efficacy.

The overall proportion of patients found to have anti-rHuPH20 antibodies remained generally constant over the follow-up period in both cohorts The clinical relevance of the development of HACAs or anti-rHuPH20 antibodies after treatment with MabThera subcutaneous formulation is not known. There was no apparent impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety or efficacy (SABRINA).

Clinical experience of MabThera concentrate for solution for infusion in Non-Hodgkin’s lymphoma

Follicular lymphoma

Initial treatment in combination with chemotherapy

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

< 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significant clinical difference (p=0.029, log-rank test stratified by 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 trials are summarized in table 3.

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

 

Treatment,

Median

 

CR,

Median

OS

Trial

FU,

ORR, %

TTF/PFS/ EFS

rates,

N

%

 

months

 

mo

%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Median TTP:

53-months

M39021

CVP, 159

14.7

71.1

R-CVP, 162

33.6

80.9

 

 

 

 

 

P<0.0001

p=0.029

 

 

 

 

 

 

 

 

 

 

 

 

Median TTF: 2.6

18-months

GLSG’00

CHOP, 205

years

R-CHOP, 223

Not reached

 

 

 

 

 

 

 

p < 0.001

p = 0.016

 

 

 

 

 

 

 

 

 

 

 

 

Median PFS: 28.8

48-months

 

MCP, 96

 

OSHO 39

Not reached

 

 

 

-

R-MCP, 105

 

p < 0.0001

 

p = 0.0096

 

CHVP-IFN,

 

 

 

Median EFS: 36

42-months

 

 

FL2000

Not reached

R-CHVP-IFN,

 

 

p < 0.0001

 

 

 

 

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.

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 observation 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). The results of the primary analysis were confirmed with longer follow-up (median observation time: 48 months) and have been added to Table 4 to show the comparison between the 25 and 48 month follow-up periods.

Table 4 Maintenance phase: overview of efficacy results MabThera vs. observation after 48 months median observation time (compared with results of primary analysis based on 25 months median observation time)

 

Observation

MabThera

Log-rank P

Risk reduction

 

N=513

N=505

value

 

 

 

 

 

 

Primary efficacy

 

 

 

 

 

PFS (median)

48.4 months

NR

<0.0001

 

45%

 

(NR)

(NR)

(<0.0001)

 

(50%)

Secondary efficacy

 

 

 

 

 

EFS (median)

47.6 months

NR

< 0.0001

 

42%

 

(37.8 months)

(NR)

(< 0.0001)

 

(46%)

OS (median)

NR

NR

0.9298

 

2%

 

(NR)

(NR)

(0.7246)

 

(11%)

TNLT (median)

60.2 months

NR

<0.0001

 

39%

 

(NR)

(NR)

(0.0003)

 

(39%)

TNCT (median)

NR

NR

(0.0006)

 

34%

 

(NR)

(NR)

(0.0011)

 

(40%)

ORR*

60.7%

79.0%

<0.0001#

 

OR=2.43

 

(55.0%)

(74.0%)

(< 0.0001)

 

(OR =2.33)

Complete Response

52.7%

72.2%

<0.0001

 

OR=2.34

(CR/CRu) rate*

(47.7%)

(66.8%)

(< 0.0001)

 

[ (OR = 2.21)

 

 

 

 

 

 

*At end of maintenance/observation; # p values from chi-squared test

Values in parentheses correspond to 25 months median observation time (primary analysis). Values outside of parentheses correspond to 48 months median observation time (updated analysis).

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, OR: odds ratio.

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/m2 body surface area given every 3 months until disease progression or for a maximum period of two years.

The final efficacy analysis included all patients randomized to both parts of the trial. 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 Reduction1)

Primary efficacy

 

 

 

 

ORR2)

74 %

87 %

0.0003

Na

CR2)

16 %

29 %

0.0005

Na

PR2)

58 %

58 %

0.9449

Na

1)Estimates were calculated by hazard ratios

2)Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of CR versus PR versus non-response (p < 0.0001)

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

For patients 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)

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 %

 

 

 

 

 

Subgroup analysis

 

 

 

 

PFS

11.6

37.5

< 0.0001

71 %

CHOP

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

NR

NR

0.0348

55 %

CHOP

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 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 overall survival for both patients responding to CHOP and patients responding to R-CHOP, although longer follow-up is required to confirm this observation.

Diffuse large B cell non-Hodgkin’s lymphoma

In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years) with diffuse large B cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1-5) every 3 weeks for eight cycles, or 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 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.

Paediatric population

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

5.2 Pharmacokinetic properties

Absorption

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 maximal concentrations about 3 days after administration. Based on popPK analysis an absolute bioavailability of 71% was estimated. Rituximab exposure increased dose proportional over the 375

mg/m2 to 800 mg/m2 subcutaneous dose range. Pharmacokinetic parameters such as clearance, distribution volume, and elimination half-life were comparable for both formulations.

Trial BP22333 (SparkThera)

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

The comparison of predicted median Cmax data for MabThera subcutaneous formulation and intravenous formulation are summarized in Table 7.

Table 7: Trial BP22333 (SparkThera): Absorption - Pharmacokinetic parameters of MabThera SC compared to MabThera IV

 

MabThera

MabThera

 

subcutaneous

intravenous

Predicted median Cmax

(q2m) µg/mL

 

 

Predicted median Cmax

(q3m) µg/mL

 

 

The median Tmax in the MabThera subcutaneous formulation was approximately 3 days as compared to the Tmax occuring 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 cycles subcutaneously during induction at 3-weekly intervals, following the first cycle of MabThera intravenous formulation, in previously untreated FL patients in combination with chemotherapy. The serum 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 the subcutaneous formulations respectively, with the resulting geometric mean ratio (Cmax, SC/Cmax, IV) of 0.941 (90% CI: 0.872, 1.015).

Distribution/Elimination

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

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

Trial BP22333 (SparkThera)

 

Geometric

 

Geometric

Geometric

 

Geometric

 

mean 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

 

subcutaneous

 

 

 

 

 

 

formulation

 

 

 

 

 

 

MabThera

25.9

 

10.9

 

intravenous

 

 

 

 

 

 

formulation

 

 

 

 

 

 

Trial BO22334 (SABRINA)

 

 

 

 

 

 

 

 

 

 

Geometric mean

 

Geometric mean

 

 

Ctrough values at pre dose cycle 8

AUC values at cycle 7

 

µg/mL

-

µg.day/mL

 

MabThera

134.6

 

 

 

 

subcutaneous

 

 

 

 

 

 

formulation

 

 

 

 

 

 

MabThera

83.1

 

 

 

 

intravenous

 

 

 

 

 

 

formulation

 

 

 

 

 

 

In a population pharmacokinetic analysis in 403 follicular lymphoma patients who received subcutaneous and/or intravenous MabThera, single or multiple infusions of MabThera as a single agent or in combination with chemotherapy, the population estimates of nonspecific clearance (CL1), initial specific clearance (CL2) likely contributed by B cells or tumour burden, and central compartment volume of distribution (V1) were 0.194 L/day, 0.535 L/day, and 4.37 L/day, respectively. The estimated median terminal elimination half-life of MabThera subcutaneous formulation was

29.7 days (range, 9.9 to 91.2 days).The analysis data set contained 6003 quantifiable samples from 403 patients administered SC and/or IV rituximab in trials BP22333 (3736 samples from 277 patients) and BO22334 (2267 samples from126 patients). Twenty nine (0.48%) post-dose observations (all from trial BP22333) were below the quantification limit. There were no missing covariate values except baseline B-cell count. Baseline tumour load was available only in trial BO22334.

Special populations

In clinical trial BO22334, an effect was observed between body size and exposure ratios reported in cycle 7, between rituximab subcutaneous formulation 1400 mg q3w and rituximab intravenous

formulation 375 mg/m2 q3w with Ctrough ratios of 2.29, 1.31, and 1.41 in patients with low, medium and 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 and sex.

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

5.3 Preclinical safety data

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

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to

100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the foetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the foetuses was observed, which persisted 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.

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

Specific studies to determine the effects of rituximab or rHuPH20 on fertility have not been performed. In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or females were observed. Additionally, no effects on semen quality were shown for rHuPH20.

In embryofetal developmental studies in mice, rHuPH20 caused reduced fetal weight and loss of implantations at systemic exposures sufficiently in excess of human therapeutic exposure.

There is no evidence of dysmorphogenesis (i.e. teratogenesis) resulting from systemic exposure to rHuPH20.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Recombinant human hyaluronidase (rHuPH20) L-histidine

L-histidine hydrochloride monohydrate ,-trehalose dihydrate

L-methionine

Polysorbate 80 Water for injections

6.2 Incompatibilities

No incompatibilities between MabThera subcutaneous formulation and polypropylene or polycarbonate syringe material or stainless steel transfer and injection needles and polyethylene Luer cone stoppers have been observed.

6.3 Shelf life

Unopened vial 30 months

After first opening

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

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

6.4 Special precautions for storage

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

For storage conditions after first opening see section 6.3.

6.5 Nature and contents of container

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

Each carton contains one vial.

6.6 Special precautions for disposal and other handling

MabThera is provided in sterile, preservative-free, non-pyrogenic, single use vials. A peel--off sticker is included on the vials which specifies the strength, route of administration and indication. This sticker should be removed from the vial and stuck onto the syringe prior to use. The following points

should be strictly adhered to regarding the use and disposal of syringes and-other medicinal sharps:

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 local requirements.

7. MARKETING AUTHORISATION HOLDER

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/067/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 2 June 1998

Date of latest renewal: 2 June 2008

10. DATE OF REVISION OF THE TEXT

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

1. NAME OF THE MEDICINAL PRODUCT

MabThera 1600 mg solution for subcutaneous injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL contains 120 mg of rituximab.

Each vial contains 1600 mg/ 13.4 mL 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 the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear to opalescent, colourless to yellowish liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

MabThera is indicated in adults in combination with chemotherapy for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia (CLL). 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.

4.2 Posology and method of administration

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

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

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

Posology

The recommended dose of MabThera subcutaneous formulation used for adult patients is a subcutaneous injection at a fixed dose of 1600 mg irrespective of the patient’s body surface area.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose 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 full intravenous dose is successfully administered.

Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent 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 given via subcutaneous injection only.The 1600 mg strength is intended for subcutaneous use in CLL only.

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are > 25 x 109/L it is recommended to administer prednisone/prednisolone 100 mg intravenous shortly before administration 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: MabThera intravenous formulation 375 mg/m2 body surface area administered on day 0 of the first cycle of treatment followed by MabThera subcutaneous formulation injected at a fixed dose of 1600 mg per cycle, on day 1 of each subsequent cycle (in total: 6 cycles). The chemotherapy should be given after MabThera administration.

---Dose 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 (see section 4.8).

Special populations

Paediatric population

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

Elderly

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

Method of administration

Subcutaneous injections

MabThera 1600 mg subcutaneous formulation should be administered as subcutaneous injection only, over approximately 7 minutes. The hypodermic injection needle must only be attached to the syringe immediately prior to administration to avoid potential needle clogging.

MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall and never 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 should be restricted to the abdominal wall.

During the treatment course with MabThera subcutaneous formulation, other medicinal products for subcutaneous 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, if appropriate.

Intravenous infusion administration

The Summary of Product Characteristics (SmPC) of MabThera 100 mg and 500 mg concentrate for solution for infusion should be referred to for information on dosing instructions and method of administration.

4.3 Contraindications

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

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

4.4 Special warnings and precautions for use

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

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

-

Progressive multifocal leukoencephalopathy

Use of MabThera may be associated with an increased risk of progressive multifocal leukoencephalopathy (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, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

If a patient develops PML, the dosing of 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.

Infusion/Administration-related reactions

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

This set of reactions which includes syndrome of cytokine release, tumor lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the 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 of the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first MabThera intravenous infusion. They were characterized by pulmonary events and in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

Severe cytokine release syndrome is characterised by severe 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.

Patients with a high tumour burden or with a high number (≥25 x 109/L) of circulating malignant cells, such as patients with CLL who may be at higher risk of especially severe cytokine release syndrome, should be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 109/L.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of 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 administration, consideration should be given to withholding 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 hypotension and bronchospasm in 10 % of patients) see section 4.8. These symptoms are usually

reversible with interruption of 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.

Administration related reactions have been observed in up to 50% of patients treated with MabThera subcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the subcutaneous injection 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 (see section 4.8).

Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical trials. Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see section 4.8). Some local cutaneous reactions occurred more than 24 hours after the MabThera subcutaneous 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 full dose of MabThera by intravenous infusion, using MabThera intravenous formulation. The highest risk of experiencing an administration related reaction is generally observed at cycle one. Beginning the therapy with MabThera intravenous infusion would allow a better handling of the administration reactions by slowing 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 full intravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

As with the intravenous formulation, MabThera subcutaneous formulation should be administered in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced healthcare professional. Premedication consisting of an analgesic/antipyretic and an antihistamine 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. A longer 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 are suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinal product administration.

Cardiac disorders

Angina pectoris, 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 109/L and/or platelet counts < 75 x 109/L as clinical experience in this population is limited. The MabThera intravenous formulation 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 patients receiving the MabThera intravenous formulation including fulminant hepatitis with fatal outcome. The majority of these patients were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that MabThera treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. At minimum this should include HBsAg-status and HBcAb-status.These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with MabThera. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Very rare cases of PML have been reported during post-marketing use of the MabThera intravenous formulation in 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.

Immunisation

The safety of immunisation 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 the MabThera intravenous formulation as 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 this has not been investigated in clinical trials.

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

Skin reactions

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

4.5 Interaction with other medicinal products and other forms of interaction

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

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 MabThera.

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.

4.6 Fertility, pregnancy and lactation

Contraception in males and females

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

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 MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3).For these reasons MabThera should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Breast-feeding

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with MabThera and for 12 months following MabThera treatment.

Fertility

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

4.7 Effects on ability to drive and use machines

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 MabThera would have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

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 MabThera intravenous formulation.

Summary of the safety profile

During the development programme, the safety profile of MabThera subcutaneous formulation was comparable to that of the intravenous formulation with the exception of local cutaneous reactions. Local cutaneous reactions including injection site reactions were very common in patients receiving MabThera subcutaneous formulation. In the NHL phase 3 trial SABRINA (BO22334), local cutaneous reactions were reported in up to 20% of patients receiving subcutaneous MabThera. The most common local cutaneous reactions in the MabThera subcutaneous arm were injection site erythema (13%), injection site pain (7%), and injection site oedema (4%). Events seen following subcutaneous administration were mild or 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). Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections. Similar events were observed in the CLL SAWYER trial (BO25341) and were reported in up to 42% of patients in the MabThera subcutaneous arm. Most common local cutaneous reactions were injection site erythema (26%), injection site pain (16%), and injection site swelling (5%).Two patients in SAWYER trial who experienced Grade 3 local cutaneous reactions (injection site erythema, injection site pain and injection site swelling).

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 -three clinical trials: SparkThera and SABRINA (the two trials in NHL) and SAWYER the CLL trial.

In trial SABRINA, severe administration-related reactions (grade≥3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation . These events were Grade 3 injection site rash and dry mouth.

In trial SparkThera, no severe administration-related reactions were reported.

In SAWYER (BO25341), severe administration-related reactions (Grade ≥3) were reported in four patients (5%) following MabThera subcutaneous administration. These events were Grade 4 thrombocytopenia and Grade 3 anxiety, injection-site erythema and urticaria.

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 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 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 disorders, 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 Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common ( 1/100 to

< 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

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

Tabulated list of adverse reactions

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

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Infections and

bacterial

sepsis,

 

serious viral

 

 

infestations

infections,

+pneumonia,

 

infection2

 

 

 

viral

+febrile infection,

 

 

 

 

 

infections,

+herpes zoster,

 

 

 

 

 

+bronchitis

+respiratory tract

 

 

 

 

 

 

infection, fungal

 

 

 

 

 

 

infections,

 

 

 

 

 

 

infections of

 

 

 

 

 

 

unknown

 

 

 

 

 

 

aetiology, +acute

 

 

 

 

 

 

bronchitis,

 

 

 

 

 

 

+sinusitis,

 

 

 

 

 

 

hepatitis B1

 

 

 

 

Blood and

neutropenia,

anaemia,

coagulation

 

transient

late neutropenia3

lymphatic

leucopenia,

+pancytopenia,

disorders,

 

increase in

 

system

+febrile

+granulocytopeni

aplastic

 

serum IgM

 

disorders

neutropenia,

a

anaemia,

 

levels3

 

 

+thrombocyt

 

haemolytic

 

 

 

 

openia

 

anaemia,

 

 

 

 

 

 

lymphadenopa

 

 

 

 

 

 

thy

 

 

 

Immune

infusion

hypersensitivity

 

anaphylaxis

tumour lysis

infusion-related

system

related

 

 

 

syndrome,

acute reversible

disorders

reactions4,

 

 

 

cytokine

thrombocytopenia

 

angioedema

 

 

 

release

 

 

 

 

 

syndrome4,

 

 

 

 

 

 

serum

 

 

 

 

 

 

sickness

 

Metabolism

 

hyperglycaemia,

 

 

 

 

and nutrition

 

weight decrease,

 

 

 

 

disorders

 

peripheral

 

 

 

 

 

 

oedema, face

 

 

 

 

 

 

oedema,

 

 

 

 

 

 

increased LDH,

 

 

 

 

 

 

hypocalcaemia

 

 

 

 

Psychiatric

 

 

depression,

 

 

 

disorders

 

 

nervousness,

 

 

 

Nervous

 

paraesthesia,

dysgeusia

 

peripheral

cranial

system

 

hypoaesthesia,

 

 

neuropathy,

neuropathy,

disorders

 

agitation,

 

 

facial nerve

loss of other

 

 

insomnia,

 

 

palsy5

senses5

 

 

vasodilatation,

 

 

 

 

 

 

dizziness, anxiety

 

 

 

 

Eye disorders

 

lacrimation

 

 

severe vision

 

 

 

disorder,

 

 

loss5

 

 

 

conjunctivitis

 

 

 

 

Ear and

 

tinnitus, ear pain

 

 

 

hearing loss5

labyrinth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

Cardiac

 

+myocardial

+left

severe cardiac

heart failure4

 

disorders

 

infarction4 and 6,

ventricular

disorders 4 and 6

and 6

 

 

 

arrhythmia,

failure,

 

 

 

 

 

+atrial

+supraventricu

 

 

 

 

 

fibrillation,

lar

 

 

 

 

 

tachycardia,

tachycardia,

 

 

 

 

 

+cardiac disorder

+ventricular

 

 

 

 

 

 

tachycardia,

 

 

 

 

 

 

+angina,

 

 

 

 

 

 

+myocardial

 

 

 

 

 

 

ischaemia,

 

 

 

 

 

 

bradycardia

 

 

 

System Organ

Very

Common

Uncommon

Rare

Very Rare

Not known

Class

Common

 

 

 

 

 

Vascular

 

hypertension,

 

 

vasculitis

 

disorders

 

orthostatic

 

 

(predominatel

 

 

 

hypotension,

 

 

y cutaneous),

 

 

 

hypotension

 

 

leukocytoclast

 

 

 

 

 

 

ic vasculitis

 

Respiratory,

 

Bronchospasm4,

asthma,

interstitial

respiratory

lung infiltration,

thoracic and

 

respiratory

bronchiolitis

lung disease7

failure4,

 

mediastinal

 

disease, chest

obliterans,

 

 

 

disorders

 

pain, dyspnoea,

lung disorder,

 

 

 

 

 

increased cough,

hypoxia

 

 

 

 

 

rhinitis

 

 

 

 

Gastrointestin

nausea

vomiting ,

abdominal

 

gastro-intestin

 

al disorders

 

diarrhoea,

enlargement

 

al perforation7

 

 

 

abdominal pain,

 

 

 

 

 

 

dysphagia,

 

 

 

 

 

 

stomatitis,

 

 

 

 

 

 

constipation,

 

 

 

 

 

 

dyspepsia,

 

 

 

 

 

 

anorexia, throat

 

 

 

 

 

 

irritation

 

 

 

 

Skin and

pruritis, rash,

urticaria,

 

 

severe bullous

 

subcutaneous

+alopecia

sweating, night

 

 

skin reactions,

 

tissue

 

sweats, +skin

 

 

Stevens-Johns

 

disorders

 

disorder

 

 

on Syndrome

 

 

 

 

 

 

toxic

 

 

 

 

 

 

epidermal

 

 

 

 

 

 

necrolysis

 

 

 

 

 

 

(Lyell’s

 

 

 

 

 

 

Syndrome) 7

 

Musculoskelet

 

hypertonia,

 

 

 

 

al, connective

 

myalgia,

 

 

 

 

tissue and

 

arthralgia, back

 

 

 

 

bone disorders

 

pain, neck pain,

 

 

 

 

 

 

pain

 

 

 

 

Renal and

 

 

 

 

renal failure4

 

urinary

 

 

 

 

 

 

disorders

 

 

 

 

 

 

General

fever , chills,

tumour pain,

infusion site

 

 

 

disorders and

asthenia,

flushing, malaise,

pain

 

 

 

administration

headache

cold syndrome,

 

 

 

 

site conditions

 

+fatigue,

 

 

 

 

 

 

+shivering,

 

 

 

 

 

 

+multi-organ

 

 

 

 

 

 

failure4

 

 

 

 

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.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50 % of patients in clinical trials involving MabThera intravenous formulation, and were predominantly seen

during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12 % of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent intravenous infusions and is <1% of patients by the eighth cycle of MabThera (containing) treatment.

Description of selected adverse reactions

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.

Localized candida infections as well as Herpes zoster were 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 hematopoietic 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 (PML) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving 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% in FC. Progression of Kaposi’s sarcoma has been observed in MabThera-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, 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 of thrombocytopenia was low (<1 %, grade 3/4) and was not different between treatment arms. During the treatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopoenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%),

grade 3/4 neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), grade 3/4 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. Studies with MabThera intravenous formulation in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1x109/L between day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who

recovered prior to day 42) following treatment with MabThera plus FC.There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of 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 adverse 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 infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).

Respiratory system

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

Neurologic disorders

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

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

Gastrointestinal disorders

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of Non-Hodgkin’s lymphoma (NHL). 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).

Skin and subcutaneous tissue disorders

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

Patient subpopulations - 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

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.

Reporting of suspected adverse reactions

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

4.9 Overdose

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

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

Three patients in the MabThera subcutaneous NHL formulation trial SABRINA (BO22334) were inadvertently adminstered subcutaneous formulation through the intravenous route up to a maximum rituximab dose of 2780 mg with no untoward effect.

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

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered substances when administered 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 cell non-Hodgkin’s lymphomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon

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

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fc receptors on the surface of granulocytes, macrophages and NK cells. Rituximab binding to 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 recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg 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 of MabThera subcutaneous formulation in chronic lymphocytic leukaemia

A two-part phase Ib, multicenter, randomized, open-label, parallel-group trial was conducted in patients with previously untreated CLL, to investigate the non-inferiority of the pharmacokinetic profile, together with efficacy and safety of MabThera subcutaneous formulation in combination with chemotherapy.

The objective of the Part 1 was to select a MabThera subcutaneous formulation dose that resulted in comparable MabThera serum Ctrough levels compared with MabThera intravenous formulation. A number of 64 patients with CLL were enrolled at any point during their treatment with MabThera intravenous formulation in combination with chemotherapy. The dose of 1600 mg of MabThera subcutaneous formulation was selected for the Part 2 of the study.

The objective of the Part 2 was to establish the non-inferiority in observed Ctrough levels between the confirmed MabThera subcutaneous dose and the reference MabThera intravenous dose.

A number of 176 patients with CLL were randomized into the following two treatment groups:

MabThera subcutaneous (n= 88); 1st cycle of MabThera intravenous 375 mg/m2 in combination with chemotherapy plus subsequent cycles (2-6) of MabThera subcutaneous 1600mg in combination with chemotherapy.

MabThera intravenous (n= 88): 1st cycle of MabThera intravenous 375 mg/m2 in combination with chemotherapy followed by up to 5 cycles of MabThera intravenous 500 mg/m2 in combination with chemotherapy.

Response rates were similar in each arm, with an overall response rate of 80.7% (95% CI: 70.9; 88.3) and 85.2% (95% CI: 76.1; 91.9) in the MabThera intravenous and subcutaneous arms, respectively. Complete response rate point estimates were 33.0% (95% CI: 23.3; 43.8) and 26.1% (95% CI: 17.3; 36.6) in the MabThera intravenous and subcutaneous arms, respectively. Overall the results confirm that MabThera subcutaneous formulation 1600 mg has a comparable benefit/risk profile to that of MabThera intravenous formulation 500 mg/m2.

Immunogenicity

Data from the development programme of MabThera subcutaneous formulation indicate that the formation of anti-rituximab antibodies (HACAs) after subcutaneous administration is comparable with that observed after intravenous administration. In SAWYER trial (BO25341) the incidence of treatment-induced/enhanced anti-rituximab antibodies was similar in the two treatment arms; 6.7% intravenous vs. 2.4% subcutaneous The incidence of treatment-induced/enhanced anti-rHuPH20 antibodies, only measured in patients in the subcutaneous arm was 10.6%. None of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies----.

---The clinical relevance of the development of anti-rituximab or anti-rHuPH20 antibodies after treatment with MabThera subcutaneous formulation is not known. There was no impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety, efficacy or PK of MabThera.

Clinical experience of MabThera concentrate for solution for infusion in CLL

In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2, days 1-3) every 4 weeks for 6 cycles or MabThera in combination with FC (R-FC). MabThera was administered at a dosage of 375 mg/m2 during the first cycle one day prior to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had previously been treated with monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 2a and Table 2b) and 552 patients (276 R-FC, 276 FC) for the relapsed/refractory study (Table 3) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p = 0.0319, log-rank test) (Table 2a). The benefit in terms of PFS was consistently observed in most patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 2b).

Table 2a First--line treatment of chronic lymphocytic leukaemia

Overview of efficacy results for MabThera plus FC vs. FC alone - 48.1 months median observation time

Efficacy Parameter

Kaplan-Meier Estimate of

Risk

 

Median Time to Event (Months)

Reduction

 

FC

R-FC

Log-Rank

 

 

(N = 409)

(N=408)

p value

 

Progression free survival

32.8

55.3

<0.0001

45%

(PFS)

 

 

 

 

Overall survival

NR

NR

0.0319

27%

Event free survival

31.3

51.8

<0.0001

44%

Response rate (CR, nPR, or PR)

72.6%

85.8%

<0.0001

n.a.

CR rates

16.9%

36.0%

<0.0001

n.a.

Duration of response*

36.2

57.3

<0.0001

44%

Disease free survival (DFS)**

48.9

60.3

0.0520

31%

Time to new treatment

47.2

69.7

<0.0001

42%

 

 

 

 

 

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

**: only applicable to patients achieving a CR

Table 2b First-line treatment of chronic lymphocytic leukaemia

Hazard ratios of progression-free survival according to Binet stage (ITT) – 48.1 months median observation time

Progression free survival (PFS)

Number of

Hazard Ratio

p-value (Wald

 

patients

(95% CI)

test, not

 

FC

R FC

 

adjusted)

Binet stage A