Active Substance: rituximab
Common Name: rituximab
ATC Code: L01XC02
Marketing Authorisation Holder: Roche Registration Ltd
Active Substance: rituximab
Authorisation Date: 1998-06-02
Therapeutic Area: Arthritis, Rheumatoid Lymphoma, Non-Hodgkin Leukemia, Lymphocytic, Chronic, B-Cell
Pharmacotherapeutic Group: Antineoplastic agents
MabThera is indicated in adults for the following indications:
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
MabThera in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed / refractory chronic lymphocytic leukaemia. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including MabThera or patients refractory to previous MabThera plus chemotherapy.
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 antirheumatic drugs (DMARDs) 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.
What is MabThera?
MabThera 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) to be given intravenously (into a vein), and as a solution for injection to be given subcutaneously (under the skin).
What is MabThera used for?
MabThera is used in adults to treat:
- Two forms of nonâ€‘Hodgkinâ€™s lymphoma (a cancer of the lymph tissue) called follicular lymphoma and diffuse large B cell non-Hodgkinâ€™s lymphoma. MabThera can be used alone or in combination with chemotherapy (medicines to treat cancer). It can be given as an intravenous or as a subcutaneous injection.
- chronic lymphocytic leukaemia (CLL, a cancer of the Bâ€‘lymphocytes: a type of white blood cell). where MabThera is used intravenously in combination with chemotherapy,
- Severe rheumatoid arthritis (a disease that causes inflammation of the joints),where MabThera is given intravenously together with methotrexate.
- two forms of severe vasculitis (inflammation of small and medium-sized blood vessels) called granulomatosis with polyangiitis (GPA or Wegenerâ€™s granulomatosis) and microscopic polyangiitis (MPA). MabThera is given intravenously together with medicines called corticosteroids.
The medicine can only be obtained with a prescription.
How is MabThera used?
MabThera should be given under the close supervision of an experienced healthcare professional. MabThera should always be given in an environment where facilities for resuscitating patients are immediately available. When it is given with chemotherapy, MabThera is given on the first day of each chemotherapy cycle. Patients should be given an antihistamine (to prevent allergic reactions) and an anti-pyretic (a medicine against fever) before each infusion. They may also need a corticosteroid as part of their treatment.
In the treatment of nonâ€‘Hodgkinâ€™s lymphoma, the usual dose of MabThera when given intravenously is 375Â mg per square metre body surface area (calculated using the patientâ€™s height and weight). The number and frequency of infusions depend on the type of lymphoma being treated. Certain patients who have received one full dose as an intravenous infusion can receive subsequent doses as a subcutaneous injection. The recommended dose for a subcutaneous injection is 1,400Â mg irrespective of the patientâ€™s body surface area.
For CLL, MabThera is given six times intravenously: the first dose is 375Â mg/m2, followed by 500Â mg/m2 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, MabThera is given as two intravenous infusions of 1,000Â 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 patientâ€™s response. Patients who receive MabThera 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 MabThera, 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, MabThera is given as an intravenous infusion of 375 mg/m2 once a week for 4 weeks.
How does MabThera work?
The active substance in MabThera, 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 Bâ€‘lymphocytes. When rituximab attaches to the antigen, this causes cell death. This helps in lymphoma and CLL, since the cancerous Bâ€‘lymphocytes are destroyed. In rheumatoid arthritis, the Bâ€‘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.
How has MabThera been studied?
MabThera has been studied in both types of nonâ€‘Hodgkinâ€™s lymphoma:
- in follicular lymphoma, MabThera 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 MabThera 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 MabThera to other types of chemotherapy. Three studies also looked at MabThera given on its own: one study looked at the overall response rate to MabThera 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 addition, MabThera given subcutaneously was compared with MabThera given intravenously in a study involving 127 patients with follicular lymphoma. MabThera was given before CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) or CVP chemotherapy and the main measure of effectiveness was based on the levels of rituximab in the blood when MabThera was given subcutaneously and intravenously, to demonstrate that sufficient levels are obtained when given subcutaneously. The study also looked at the percentage of patients who responded completely or partially to treatment. Response to treatment was assessed using body scans and patientsâ€™ clinical data.
- in diffuse large Bâ€‘cell lymphoma, the effectiveness of adding MabThera 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 MabThera to â€˜FCâ€™ 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 MabThera to other types of chemotherapy.
In rheumatoid arthritis, MabThera was studied in 517 patients. The effectiveness of adding MabThera 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, MabThera 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 MabThera shown during the studies?
In nonâ€‘Hodgkinâ€™s lymphoma, patients receiving MabThera had better outcomes than those not receiving it:
- in follicular lymphoma, patients receiving MabThera 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 MabThera to other types of chemotherapy also improved the patientsâ€™ outcomes. In the studies of MabThera given on its own, 48% of the patients who had failed previous treatment responded to MabThera. The maintenance study in patients whose disease had come back after previous treatment showed that patients who received MabThera 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. When MabThera was given subcutaneously, the levels of the active substance were comparable to the levels of Mabthera given intravenously. The response rate for patients who received MabThera subcutaneously was also similar to the rate in patients who received MabThera intravenously.
- in diffuse large Bâ€‘cell lymphoma, patients adding MabThera to â€˜CHOPâ€™ 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 â€˜CHOPâ€™ alone.
In CLL, patients also had better outcomes when they received MabThera. Those who had not been treated before lived for an average of 39.8 months without their disease getting worse when they received MabThera 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 MabThera 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 MabThera to other types of chemotherapy also improved the outcome of patients with CLL.
In rheumatoid arthritis, MabThera was more effective than placebo: 51% of the patients receiving MabThera had an improvement in symptoms, compared with 18% of the patients receiving placebo.
In GPA and MPA, 64% of patients given MabThera (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 MabThera?
When used to treat nonâ€‘Hodgkinâ€™s lymphoma or CLL, the most common side effects with MabThera (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.
In the study comparing MabThera given subcutaneously and intravenously, side effects were comparable apart from reactions around the injections site (pain, swelling, rash) which occurred more frequently when given subcutaneously. For the full list of all side effects reported with MabThera , see the package leaflet.
MabThera must not be used in people who are hypersensitive (allergic) to rituximab, mouse proteins or any of the other ingredients. The formulation of MabThera for subcutaneous use must also not be used in patients who are allergic to a substance called hyaluronidase. MabThera 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 MabThera if they have severe heart failure (an inability of the heart to pump enough blood around the body) or severe heart disease.
Why has MabThera been approved?
The Committee for Medicinal Products for Human Use (CHMP) decided that MabTheraâ€™s benefits are greater than its risks and recommended that it be given marketing authorisation.
Other information about MabThera
The European Commission granted a marketing authorisation valid throughout the European Union for MabThera on 2 June 1998.
Source: European Medicines Agency
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