MabThera

/ Roche

Non-Hodgkin’s lymphoma
Dosage adjustments during treatment: No dose reductions of Rituximab are recommended. When Rituximab is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.
Follicular non-Hodgkin’s lymphoma
Combination Therapy: The recommended dose of Rituximab 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. This drug 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 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 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 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 monotherapy for patients who have responded to previous treatment with Rituximab 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.
Diffuse large B cell non-Hodgkin’s lymphoma: This drug 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 Rituximab have not been established in combination with other chemotherapies in diffuse large B cell non- Hodgkin’s lymphoma.
Chronic lymphocytic leukaemia: Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are > 25 x 109/L it is recommended to administer prednisone/prednisolone 100 mg intravenous shortly before infusion with Rituximab to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome. The recommended dosage 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 Rituximab infusion.
Rheumatoid arthritis: Patients should receive treatment with 100 mg intravenous methylprednisolone to be completed 30 minutes prior to Rituximab infusions to decrease the incidence and severity of infusion related reactions. Premedication consisting of an analgesic/anti-pyretic (e.g. paracetamol) and an antihistaminic drug (e.g. diphenhydramine) should always be administered before each infusion. A course consists of two 1000 mg intravenous infusions. The recommended dosage is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later. Subsequent courses should be administrated every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. 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.
First infusion of each course: The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
Second infusion of each course: Subsequent doses can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minute intervals, to a maximum of 400 mg/hr.
Granulomatosis with polyangiitis and Microscopic polyangiitis: Premedication consisting of an analgesic/anti-pyretic (e.g. paracetamol) and an anti-histaminic drug (e.g. diphenhydramine) should always be administered before each infusion. The recommended dosage for treatment 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). Methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion (the last dose of ethylprednisolone may be given on the same day as the first infusion). This should be followed by oral prednisone 1 mg/kg/day (not to exceed 80mg/day, and tapered as rapidly as possible based on clinical need) during and after Rituximab treatment.
First infusion: The recommended initial infusion rate is 50 mg/h; subsequently, the rate can be escalated in 50 mg/h increments every 30 minutes to a maximum of 400 mg/h. Subsequent infusions (number 2 to 4): Subsequent infusions can be started at a rate of 100 mg/h and increased by 100 mg/h increments every 30 minutes to a maximum of 400 mg/h. Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with Granulomatosis with polyangiitis or Microscopic polyangiitis during and following treatment, as appropriate.
Special Populations:
Paediatric population: The safety and efficacy of MabThera in children has not been established.
Older people: No dose adjustment is required in elderly patients (aged >65 years).
Method of administration: Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be administered before each infusion. In Rheumatoid Arthritis, premedication with glucocorticoids should also be administered in order to reduce the frequency and severity of infusion-related reactions. Premedication with glucocorticoids should be considered if Rituximab is not given in combination with glucocorticoid-containing chemotherapy for treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.
First infusion: The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
Subsequent infusions: Subsequent doses of Rituximab can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minute intervals, to a maximum of 400 mg/hr. The prepared 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.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 normalization 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. Usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.

Non-Hodgkin’s lymphoma (NHL): Treatment of relapsed or refractory low-grade or follicular B-cell non-Hodgkin’s lymphoma. Treatment of previously untreated patients with low grade or follicular lymphoma in combination with chemotherapy. Treatment of patients with CD₂O positive diffuse large B-cell non-Hodgkin’s lymphoma in combination with CHOP chemotherapy. Maintenance therapy for the treatment of follicular lymphoma patients responding to induction therapy.
Chronic lymphocytic leukemia (CLL): In combination with chemotherapy 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, or patients refractory to previous MabThera plus chemotherapy.
Rheumatoid arthritis: To reduce signs and symptoms in adult patients with moderately to severe active rheumatoid arthritis who had an inadequate response or intolerance to one or more TNF antagonist therapies, in combination with methotrexate.
ANCA-Associated Vasculitis (AAV): Treatment of adults with Wegener’s Granulomatosis (WG) and Microscopic Polyantiitis (MPA), in combination with glucocorticoids.

For use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia: Hypersensitivity to the active substance or to any of the excipients. Active, severe infections. Patients in a severely immune-compromised state.
Contraindications for use in rheumatoid arthritis, Granulomatosis with polyangiitis and Microscopic polyangiitis: Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease.

In order to improve traceability of biological medicinal products, the tradename of the administered product should be clearly recorded (or stated) in the patient file.
Progressive multifocal leukoencephalopathy: 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 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. 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 IV 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. 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 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 only be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 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). 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.
For full details see prescribing information.

Bacterial, viral infections, neutropenia, leucopenia, febrile neutropenia, thrombocytopenia, nausea, pruritus, rash, hypertension, orthostatic hypotension, hypotension bronchospasm, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis, vomiting , diarrhoea,, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation, urticaria, sweating, night, sweats,  skin disorder.
For full details see prescribing information.

See prescribing information for full details.

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. 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.

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 chronic lymphocytic leukaemia. 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.