Presentation and Status in Health Basket
2 X 10 ml
1 X 50 ml
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be given before each administration of Rituximab.
In patients with CLL, premedication with glucocorticoids should be considered if Rituximab is not given in combination with glucocorticoid-containing chemotherapy.
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 Rituximab (the last dose of methylprednisolone may be given on the same day as the first infusion of Rituximab). 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 Rituximab treatment.
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 of Rituximab 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.
Granulomatosis with polyangiitis and microscopic polyangiitis: The recommended dosage of Rituximabfor 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 Rituximab treatment, as appropriate.
Elderly: No dose adjustment is required in elderly patients (aged >65 years).
Paediatric population: The safety and efficacy of rituximab in children below 18 years has not been established. No data are available.
For method of administration: The prepared Truxima 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. 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 (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 Truxima 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.
Chronic lymphocytic leukaemia (CLL):: 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 rituximab or patients refractory to previous rituximab plus chemotherapy.
Granulomatosis with polyangiitis and microscopic polyangiitis: In combination with glucocorticoids, is indicated for the treatment of adult patients with granulomatosis with polyangiitis (GPA) (Wegener’s Granulomatosis (WG)) and microscopic polyangiitis (MPA).
For use in chronic lymphocytic leukaemia: Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients.
Active, severe infections.
Patients in a severely immunocompromised state.
For use in granulomatosis with polyangiitis and microscopic polyangiitis: Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients.
Active, severe infections.
Patients in a severely immunocompromised state.
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 and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Progressive multifocal leukoencephalopathy (PML): Very rare cases of fatal PML have been reported following the use of rituximab. 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 Truxima 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 Rituximab therapy may lead to similar stabilisation or improved outcome.
Chronic lymphocytic leukaemia: Infusion related reactions: Rituximab 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 rituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first rituximab intravenous infusion.
Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema.
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 10^9/L.
Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with rituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10 % of patients).
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.
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.
Since hypotension may occur during Rituximab administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the Rituximab 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 rituximab. Therefore, patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.
Haematological toxicities: Although Rituximab is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 x 10^9/L and/or platelet counts < 75 x 10^9/L as clinical experience in this population is limited. Rituximab 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 Rituximab therapy.
Infections: Serious infections, including fatalities, can occur during therapy with Rituximab. Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections.
Cases of hepatitis B reactivation have been reported in subjects receiving rituximab including fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic chemotherapy.
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of rituximab in CLL .The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant.
Immunisations: The safety of immunisation with live viral vaccines, following Rituximab therapy has not been studied for CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with Rituximab may receive non-live vaccinations. However, with non-live vaccines response rates may be reduced.
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 rituximab.
Skin reactions: Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal outcome, have been reported. In case of such an event, with a suspected relationship to Rituximab, treatment should be permanently discontinued.
Granulomatosis with polyangiitis and microscopic polyangiitis: Infusion related reactions: Rituximab 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 medicinal product and an anti-histaminic medicinal product, should always be administered before each infusion of Rituximab.
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 . The reactions reported were usually reversible with a reduction in rate, or interruption, of rituximab 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 Rituximab.
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 Rituximab.
There are no data on the safety of Rituximab in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, 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 Rituximab and patients closely monitored during administration. Since hypotension may occur during rituximab infusion, consideration should be given to withholding anti-hypertensive medicinal product 12 hours prior to the Rituximab 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 rituximab. Therefore patients with a history of cardiac disease should be monitored closely.
Infections: Based on the mechanism of action of Rituximab and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infection following Rituximab therapy. Serious infections, including fatalities, can occur during therapy with Rituximab .Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low).
Patients reporting signs and symptoms of infection following Rituximab therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of Rituximab 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 rituximab 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 granulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Rituximab. 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 Rituximab. 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 Rituximab, and regularly up to 6-months after cessation of treatment, and upon signs or symptoms of infection.
Skin reactions: Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal outcome, have been reported. In case of such an event with a suspected relationship to Rituximab, treatment should be permanently discontinued.
Immunisation: Physicians should review the patient’s vaccination status and follow current immunisation guidelines prior to Rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration of Rituximab.
The safety of immunisation with live viral vaccines following Rituximab therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on Rituximab or whilst peripherally B cell depleted.
Patients treated with Rituximab may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced.
Malignancy: Immunomodulatory medicinal products may increase the risk of malignancy. 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.
See prescribing information for full details.
The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab were IRRs (including cytokine-release syndrome, tumour-lysis syndrome) 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 rituximab.
Infectious events (predominantly bacterial and viral) occurred in approximately 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).
Other serious ADRs reported include hepatitis B reactivation and PML.
See prescribing information for full details.
Currently, there are limited data on possible medicinal product interactions with Truxima.
In CLL patients, co-administration with rituximab 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 rituximab.
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.
Pregnancy and Lactation
Pregnancy: IgG immunoglobulins are known to cross the placental barrier.
B cell levels in human neonates following maternal exposure to Truxima 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 rituximab during pregnancy. Similar effects have been observed in animal studies. For these reasons Truxima should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
Lactation: 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 Truxima and for 12 months following Truxima treatment.
Limited experience with doses higher than the approved dose of intravenous rituximab formulation is available from clinical trials in humans. The highest intravenous dose of rituximab 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 post-marketing setting five cases of rituximab 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.
Incompatibilities: No incompatibilities between rituximab and polyvinyl chloride or polyethylene bags or infusion sets have been observed.
Shelf life: Unopened vial: The expiry date of the product is indicated on the packaging materials.
Diluted product: 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.
The prepared infusion solution of rituximab is physically and chemically stable for 24 hours at 2 °C – 8 °C and subsequently 12 hours at room temperature (not more than 30 °C).
Storage: Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from light.