In non-hodgkin s lymphoma, MabThera is used to treat two types of the disease, both of which affect B-lymphocytes:

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1 EMA/614203/2010 EMEA/H/C/ EPAR summary for the public rituximab This is a summary of the European public assessment report (EPAR) for. It explains how the Committee for Medicinal Products for Human Use (CHMP) assessed the medicine to reach its opinion in favour of granting a marketing authorisation and its recommendations on the conditions of use for. What is? is a medicine that contains the active substance rituximab. It is available as a concentrate that is made up into a solution for infusion (drip) into a vein. What is used for? is used in adults to treat non-hodgkin s lymphoma (a cancer of the lymph tissue), chronic lymphocytic leukaemia (CLL, a cancer of the B-lymphocytes, a type of white blood cell), rheumatoid arthritis (a disease that causes inflammation of the joints) and two forms of vasculitis (inflammation of small and medium-sized blood vessels) called granulomatosis with polyangiitis (GPA or Wegener s granulomatosis) and microscopic polyangiitis (MPA). In non-hodgkin s lymphoma, is used to treat two types of the disease, both of which affect B-lymphocytes: in follicular lymphoma, is used in combination with chemotherapy (medicines to treat cancer) in patients with advanced disease who have not been treated before. It can also be used as maintenance treatment in patients whose follicular lymphoma has responded to initial chemotherapy. It is also used on its own in patients with advanced disease who are resistant to chemotherapy or who have failed two or more chemotherapy treatments; in patients with diffuse large B-cell lymphoma, is used in combination with a specific type of chemotherapy called CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone). 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom Telephone +44 (0) Facsimile +44 (0) info@ema.europa.eu Website An agency of the European Union European Medicines Agency, Reproduction is authorised provided the source is acknowledged.

2 In CLL, is used in combination with chemotherapy in patients who have not been treated before and in patients whose disease has come back after previous treatment. In rheumatoid arthritis, is used in adults with severe disease in combination with methotrexate (a medicine that acts on the immune system). It is used in patients who cannot take or have not responded adequately to other treatments for rheumatoid arthritis, including a tumour necrosis factor (TNF) inhibitor. In GPA and MPA, is used in adults with severe disease in combination with medicines called corticosteroids. The medicine can only be obtained with a prescription. How is used? should be given under the close supervision of an experienced doctor, and in an environment where facilities for resuscitating patients are immediately available. When it is given with chemotherapy, is given on the first day of each chemotherapy cycle. Patients should be given an antihistamine (to prevent allergic reactions) and an analgesic / anti-pyretic (a medicine against pain and fever) before each infusion. They may also need a corticosteroid as part of their treatment. In the treatment of non-hodgkin s lymphoma, the usual dose of is 375 mg per square metre body surface area (calculated using the patient s height and weight). The number and frequency of infusions depend on the type of lymphoma being treated. For CLL, is given six times: the first dose is 375 mg/m 2, followed by 500 mg/m 2 for the remaining doses. To prevent side effects caused by destruction of the cancerous lymphocytes, patients need to be well hydrated and treated with medicines that help to stabilise uric acid levels before treatment. For rheumatoid arthritis, is given as two infusions of 1,000 mg with a two-week interval between them. Patients usually respond to treatment within 16 to 24 weeks of initial treatment. After 24 weeks, treatment can be repeated depending on the patient s response. Patients who receive for rheumatoid arthritis and GPA/MPA must be given a special card that explains the symptoms of certain types of infection that can occur as a side effect of, instructing patients to seek medical care immediately if they experience them. See the summary of product characteristics (also part of the EPAR) for full details. For GPA and MPA, is given as an infusion of 375 mg/m 2 once a week for 4 weeks. How does work? The active substance in, rituximab, is a monoclonal antibody. A monoclonal antibody is an antibody (a type of protein) that has been designed to recognise and attach to a specific structure (called an antigen) that is found on certain cells in the body. Rituximab has been designed to target an antigen called CD20, which is present on the surface of B-lymphocytes. When rituximab attaches to the antigen, this causes cell death. This helps in lymphoma and CLL, since the cancerous B-lymphocytes are destroyed. In rheumatoid arthritis, the B-lymphocytes are destroyed in the joints, helping to reduce inflammation. In GPA and MPA destroying the B-lymphocytes lowers the production of antineutrophil cytoplasmic antibodies (ANCA), a type of antibody thought to play an important role in attacking the blood vessels, and reduces the inflammation. EMA/276006/2013 Page 2/5

3 How has been studied? has been studied in both types of non-hodgkin s lymphoma: in follicular lymphoma, has been studied in one main study involving 322 patients whose follicular lymphoma had not been treated before. This study looked at the effectiveness of adding to standard chemotherapy (CVP: cyclophosphamide, vincristine and prednisolone) by measuring how long the patients lived without the disease coming back. Three further studies from the published scientific literature looked at the effects of adding to other types of chemotherapy. Three studies also looked at given on its own: one study looked at the overall response rate to in 203 patients who had failed previous treatments and the other two studies were maintenance studies in a total of 1,353 patients (334 patients whose disease had come back after previous treatment and 1,019 previously untreated patients), looking at how long the patients lived without the disease getting worse; in diffuse large B-cell lymphoma, the effectiveness of adding to CHOP chemotherapy was examined in a study involving 399 patients who were all over 60 years of age. The main measure of effectiveness was how long the patients lived without the disease getting worse or the need for a change in treatment. In CLL, the effectiveness of adding to FC chemotherapy (fludarabine and cyclophosphamide) was studied in 817 patients who had not been treated before and in 552 whose disease had come back after previous treatment. The main measure of effectiveness was how long the patients lived without their disease getting worse. Additional studies from the published scientific literature looked at the effects of adding to other types of chemotherapy. In rheumatoid arthritis, was studied in 517 patients. The effectiveness of adding to methotrexate was compared with that of adding placebo (a dummy treatment). The study measured how many patients had experienced a 20% improvement in the key symptoms of rheumatoid arthritis after 24 weeks. In GPA and MPA, was compared with cyclophosphamide, another medicine for vasculitis, in a single study lasting 18 months in 198 new or previously treated patients (about three-quarters of whom had GPA). The main measure of effectiveness was the number of patients who were free from signs of disease (complete remission), and needed no further corticosteroid treatment, six months after the start of the study. What benefit has shown during the studies? In non-hodgkin s lymphoma, patients receiving had better outcomes than those not receiving it: in follicular lymphoma, patients receiving in addition to CVP chemotherapy lived for an average of 25.9 months without the disease coming back, compared with 6.7 months in those receiving CVP alone. The three additional studies also showed that adding to other types of chemotherapy also improved the patients outcomes. In the studies of given on its own, 48% of the patients who had failed previous treatment responded to. The maintenance study in patients whose disease had come back after previous treatment showed that patients who received lived for an average of 42.2 months without the disease getting worse, compared with 14.3 months in patients who did not receive the medicine. The maintenance study in previously untreated patients showed the likelihood for the disease to get worse was reduced by 50% for patients who received Mabthera; EMA/276006/2013 Page 3/5

4 in diffuse large B-cell lymphoma, patients adding to CHOP chemotherapy lived for an average of 35 months without the disease getting worse or the need for a change in treatment, compared with 13 months in those receiving CHOP alone. In CLL, patients also had better outcomes when they received. Those who had not been treated before lived for an average of 39.8 months without their disease getting worse when they received in addition to FC, compared with 32.2 months in patients receiving FC alone. In patients whose disease had come back after previous treatment, those receiving in addition lived for 30.6 months without their disease getting worse, compared with 20.6 months in those receiving FC alone. The additional studies also showed that adding to other types of chemotherapy also improved the outcome of patients with CLL. In rheumatoid arthritis, was more effective than placebo: 51% of the patients receiving had an improvement in symptoms, compared with 18% of the patients receiving placebo. In GPA and MPA, 64% of patients given (63 out of 98) were in complete remission after six months, compared with 55% given cyclophosphamide (52 out of 95). What is the risk associated with? When used to treat non-hodgkin s lymphoma or CLL, the most common side effects with (seen in more than 1 patient in 10) are bacterial infections, viral infections, bronchitis (inflammation of the airways in the lungs), neutropenia (low levels of neutrophils, a type of white blood cell), leucopenia (low white blood cell counts), febrile neutropenia (neutropenia with fever), thrombocytopenia (low blood platelet counts), reactions related to the infusion (mainly fever, chills and shivering), angioedema (swelling beneath the skin), nausea (feeling sick), pruritus (itching), rash, alopecia (hair loss), fever, chills, asthenia (weakness), headache and decreased levels of IgG (a type of antibody). When used to treat rheumatoid arthritis, the most common side effects (seen in more than 1 patient in 10) are headache, upper respiratory tract infection (colds), urinary tract infection (infection of the structures that carry urine), reactions related to the infusion. When used for GPA or MPA, the most common side effects (seen in more than 1 patient in 10) are diarrhoea, peripheral oedema (swelling of the ankles and feet), muscle spasms, joint and back pain, dizziness, tremor, insomnia, cough, dyspnoea (difficulty breathing), nose bleeds, and hypertension (increased blood pressure); some of these may occur as part of reactions related to the infusion. For the full list of all side effects reported with, see the package leaflet. must not be used in people who are hypersensitive (allergic) to rituximab, mouse proteins or any of the other ingredients. It must not be used in patients who have an active severe infection or a severely weakened immune system. In addition, patients with rheumatoid arthritis, GPA or MPA must not receive if they have severe heart failure (an inability of the heart to pump enough blood around the body) or severe heart disease. Why has been approved? The Committee for Medicinal Products for Human Use (CHMP) decided that s benefits are greater than its risks and recommended that it be given marketing authorisation. Other information about The European Commission granted a marketing authorisation valid throughout the European Union for on 2 June EMA/276006/2013 Page 4/5

5 The full EPAR for can be found on the Agency s website ema.europa.eu/find medicine/human medicines/european Public Assessment Reports. For more information about treatment with, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist. This summary was last updated in EMA/276006/2013 Page 5/5