Redditux

Rituximab.

Rituximab (Redditux) is available in 10 mL vial containing 100 mg of Rituximab (r-DNA origin) or 50 mL vial containing 500 mg of Rituximab (r-DNA origin).
Active substance: Rituximab (r-DNA origin).
Rituximab is a genetically engineered mouse-human chimeric monoclonal antibody representing a glycosylated immunoglobulin that contains murine light and heavy chain variable regions and human IgG1 constant region sequences. The antibody is produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchange chromatographies, including specific viral inactivation and removal procedures.
Excipients with known effects: This medicinal product contains less than 1mmol sodium per dose, i.e. essentially sodium free.
Excipients/Inactive Ingredients: Sodium citrate, Polysorbate 80, Sodium chloride, Water for injection.

Pharmacotherapeutic group: Monoclonal antibodies. ATC code: L01X C02.
Pharmacology: Pharmacodynamics: 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 >90 % of all B cell non-Hodgkin's Lymphomas (NHLs). 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 Fcγ 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 rituximab. 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 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.
Pharmacokinetics: Non-Hodgkin's lymphoma: Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of rituximab as a single agent or in combination with CHOP therapy (applied rituximab 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 rituximab 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 rituximab 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 rituximab. This analysis suggests that dose adjustment of rituximab with any of the tested covariates is not expected to result in a meaningful reduction in its pharmacokinetic variability.
Rituximab, 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 rituximab, yielded a mean C_max 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 rituximab at a dose of 375 mg/m² as an intravenous infusion at weekly intervals for 8 doses to 37 patients with NHL, the mean C_max 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 rituximab when administered as 6 infusions of 375 mg/m² in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.
Chronic lymphocytic leukaemia: Rituximab was administered as an IV 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 C_max (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).
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 Rituximab 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.
Toxicology: Preclinical safety data: Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies reported with rituximab 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 with rituximab have been performed in cynomolgus monkeys at dosages 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 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.

Non-Hodgkin's lymphoma (NHL): Rituximab (Redditux) is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.
Rituximab (Redditux) maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Rituximab (Redditux) 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.
Rituximab (Redditux) 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): Rituximab (Redditux) 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 rituximab or patients refractory to previous rituximab plus chemotherapy.
Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA): Rituximab (Redditux), in combination with glucocorticoids, is indicated for the treatment of adult patients with severe, active granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA).
Moderate to severe Pemphigus Vulgaris (PV) in adult patients: Rituximab (Redditux) is indicated for the treatment of patients with moderate to severe pemphigus vulgaris (PV).

Rituximab (Redditux) should only be administered under close supervision by an experienced medical person in a facility where immediate resuscitation measures are available.
Premedication and Prophylactic medications: 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.
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be administered before each infusion of Rituximab (Redditux).
In patients with non-Hodgkin's lymphoma and chronic lymphocytic leukaemia, premedication with glucocorticoids should be considered if Rituximab (Redditux) is not given in combination with glucocorticoid containing chemotherapy.
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.
In patients with granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis in disease remission or pemphigus vulgaris, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to Redditux 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 Rituximab (Redditux) (the last dose of methylprednisolone may be given on the same day as the first infusion of Rituximab (Redditux)). 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 the 4 week induction course of Rituximab (Redditux) treatment.
Pneumocystis jirovecii pneumonia (PCP) prophylaxis is recommended for patients with GPA/MPA or PV during and following Rituximab (Redditux) treatment, as appropriate according to local clinical practice guidelines.
Posology: Follicular non-Hodgkin's lymphoma: Combination therapy: The recommended dose of Rituximab (Redditux) in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular NHL is: 375 mg/m² body surface area per cycle, for up to 8 cycles.
Rituximab (Redditux) 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 Rituximab (Redditux) 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 Rituximab (Redditux) 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 Rituximab (Redditux) 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 Rituximab (Redditux) monotherapy for patients who have responded to previous treatment with Redditux 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: Rituximab (Redditux) 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.
Dosage adjustments during treatment: No dose reductions of Rituximab (Redditux) are recommended. When Rituximab (Redditux) is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.
Chronic lymphocytic leukaemia: The recommended dosage of Rituximab (Redditux) 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: Induction of remission: The recommended dosage of Rituximab (Redditux) 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).
Maintenance treatment: Following induction of remission with Rituximab (Redditux), maintenance treatment should be initiated no sooner than 16 weeks after the last Rituximab (Redditux) infusion.
Following induction of remission with other standard of care immunosuppressants, Rituximab (Redditux) maintenance treatment should be initiated during the 4 week period that follows disease remission.
Rituximab (Redditux) should be administered as two 500 mg IV infusions separated by two weeks, followed by a 500 mg IV infusion every 6 months thereafter. Patients should receive Rituximab (Redditux) for at least 24 months after achievement of remission (absence of clinical signs and symptoms). For patients who may be at higher risk for relapse, physicians should consider a longer duration of Rituximab (Redditux) maintenance therapy, up to 5 years.
Pemphigus vulgaris: The recommended dosage of Rituximab (Redditux) for the treatment of pemphigus vulgaris is 1000 mg administered as an IV infusion followed two weeks later by a second 1000 mg IV infusion in combination with a tapering course of glucocorticoids.
Maintenance treatment: A maintenance infusion of 500 mg IV should be administered at months 12 and 18, and then every 6 months thereafter if needed, based on clinical evaluation.
Treatment of relapse: In the event of relapse, patients may receive 1000 mg IV. The healthcare provider should also consider resuming or increasing the patient's glucocorticoid dose based on clinical evaluation.
Subsequent infusions may be administered no sooner than 16 weeks following the previous infusion.
Special populations: Paediatric use: Safety and efficacy of rituximab is not established below the age of 18 yrs.
Elderly: No dose adjustment is required in elderly patients (aged >65 years).
Method of Administration: The prepared Rituximab (Redditux) 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 Precautions). 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 (see Adverse Reactions) 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/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 Redditux can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr.

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 chronic lymphocytic leukaemia. No additional safety signals were identified.
Three patients in the rituximab 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 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.

Contraindications for use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia: Hypersensitivity to the active substance or to any of the excipients or to murine proteins.
Active, severe infections (see Precautions).
Patients in a severely immunocompromised state.
Contraindications for use in granulomatosis with polyangiitis, microscopic polyangiitis and pemphigus vulgaris: Hypersensitivity to the active substance or to any of the excipients (as mentioned in Description) or to murine proteins.
Active, severe infections (see Precautions).
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.
Methotrexate: The use of Rituximab is not recommended in MTX-naive patients.
Progressive Multifocal Leukoencephalopathy: Use of rituximab may be associated with an increased risk of Progressive Multifocal Leukoencephalopathy (PML). Very rare cases of fatal PML have been reported following 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, 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 rituximab must be permanently discontinued.
Following reconstitution of the immune system in immunocompromised patients with PML, stabilization or improved outcome has been seen. It remains unknown if early detection of PML and suspension of rituximab therapy may lead to similar stabilization or improved outcome.
Non-Hodgkin's lymphoma and 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 as follows. They are not specifically related to the route of administration of Rituximab and can be observed with both formulations.
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 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.
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.
Severe cytokine release syndrome is characterized 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. Severe, including fatal, renal toxicity can occur after rituximab administered in patients with NHL. 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 Dosage & Administration) 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.
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) see Adverse Reactions. These symptoms are usually reversible with interruption of rituximab 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 previously 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 rituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (described previously). 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 rituximab infusion, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the rituximab infusion.
Cardiac disorders: Angina pectoris or 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 10⁹/l and/or platelet counts < 75 x 10⁹/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 (see Adverse Reactions). Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see Contraindications).
Physicians should exercise caution when considering the use of rituximab in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see Adverse Reactions).
Cases of hepatitis B reactivation have been reported in subjects receiving rituximab including fulminant hepatitis with fatal outcomes, hepatic failure and deaths. The majority of these subjects were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that rituximab 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 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.
Very rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported during post-marketing use of Rituximab in NHL and CLL (see Adverse Reactions). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.
Immunizations: The safety of immunization with live viral vaccines, following rituximab therapy has not been studied for NHL and 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. In a non-randomized study, patients with relapsed low-grade NHL who received rituximab 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 titers 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 (see Adverse Reactions). In case of such an event, treatment should be permanently discontinued.
Granulomatosis with polyangiitis and microscopic polyangiitis, and pemphigus vulgaris: IRRs for patients with granulomatosis with polyangiitis, microscopic polyangiitis and pemphigus vulgaris were consistent with those seen for rheumatoid arthritis patients.
Infusion related reactions: Rituximab is associated with infusion related reactions (IRR), which may be related to release of cytokines and/or other chemical mediators.
Severe infusion-related reactions with fatal outcome have been reported in Rheumatoid arthritis patients in the post-marketing setting. Most infusion events reported 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 Adverse Reactions). 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 infusion-related reaction and the required interventions, temporarily or permanently discontinue rituximab. 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 rituximab. The presence of HACA may be associated with worsening of infusion or allergic reactions after the second infusion of subsequent courses.
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, 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 medications 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 (see Infusion related reactions, previously).
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 (see Adverse Reactions). Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see Contraindications) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of rituximab 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 Adverse Reactions). It is recommended that immunoglobulin levels are determined prior to initiating treatment with rituximab.
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 Progressive Multifocal Leukoencephalopathy (PML) have been reported following use of rituximab for the treatment of autoimmune diseases including Systemic Lupus Erythematosus (SLE) and Vasculitis. These cases involved patients with multiple risk factors for PML, including the underlying disease and long-term immunosuppressive therapy or chemotherapy.
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 (see Adverse Reactions).
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 Adverse Reactions). In case of such an event, treatment should be permanently discontinued.
Immunization: Physicians should review the patient's vaccination status and follow current immunization guidelines prior to rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration of rituximab.
The safety of immunization 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.
Excipients: This medicinal product contains 2.27 mmol (or 52.26 mg) sodium per 10 mL vial and 11.36 mmol (or 261.34 mg). To be taken into consideration by patients on a controlled sodium diet.
Effects on ability to drive and use machines: No studies on the effects of rituximab on the ability to drive and use machines have been performed, although the pharmacological activity and adverse reactions reported to date suggest that rituximab would have no or negligible influence on the ability to drive and use machines.

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 Redditux.
Pregnancy: IgG immunoglobulins are known to cross the placental barrier. B cell levels in human neonates following maternal exposure to rituximab 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. For these reasons rituximab should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during treatment and for 12 months following rituximab therapy.
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 rituximab and for 12 months following rituximab treatment.
Fertility: Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

Experience from non-Hodgkin's lymphoma and chronic lymphocytic leukaemia: Summary of the safety profile: The overall safety profile of rituximab in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with rituximab 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 rituximab 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 rituximab.
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 Precautions.
Infections, see Precautions.
Cardiovascular events, see Precautions.
Other serious ADRs reported include hepatitis B reactivation and PML (see Precautions).
The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy are summarised in the tables as follows. 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) and very rare (<1/10,000). The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under "not known". (See Table 1.)

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The following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the rituximab arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.
Description of selected adverse reactions: Infusion-related reactions: 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 and pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac events (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, acute respiratory distress syndrome, ventricular fibrillation, cardiogenic shock 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 rituximab (containing) treatment.
Infections: Rituximab 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 was reported at a higher incidence in the rituximab-containing arm of randomized studies. Severe infections were reported in about 4 % of patients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during rituximab 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 rituximab treatment. The majority of patients had received rituximab 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 (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 subjects receiving rituximab 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 rituximab-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 rituximab 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 rituximab 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. In studies with rituximab 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 rituximab 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 rituximab 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 rituximab 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 thrombocytopenias was reported in 11 % of patients in the R-FC group compared to 9 % of patients in the FC group.
In studies of rituximab 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 rituximab 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 rituximab 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 rituximab compared to <1 % on observation. In studies evaluating rituximab 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 rituximab 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 events: During the treatment period, 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 % RFC, 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: Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituximab in combination with chemotherapy. ln postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.
IgG levels: In the clinical trial evaluating rituximab maintenance treatment, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction treatment in both the observation and the rituximab groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the rituximab group. The proportion of patients with IgG levels below the LLN was about 60 % in the rituximab 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 rituximab, 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 - Rituximab 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 rituximab was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).
Patient subpopulations - Rituximab 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 granulomatosis with polyangiitis and microscopic polyangiitis: Induction of remission: Ninety-nine patients were treated for induction of remission of GPA and MPA in an innovator's clinical trial with rituximab (375 mg/m², once weekly for 4 weeks) and glucocorticoids (see Pharmacology: Pharmacodynamics under Actions).
The ADRs listed in Table 2 were all adverse events which occurred at an incidence of ≥ 5% in the rituximab group and at a higher frequency than the comparator group. (See Table 2.)

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Maintenance treatment: In a further clinical study, a total of 57 severe, active GPA and MPA patients in disease remission were treated with rituximab for the maintenance of remission. (See Table 3.)

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The overall safety profile was consistent with the well-established safety profile for rituximab in approved autoimmune indications, including GPA/MPA. Overall, 4% of patients in the rituximab arm experienced adverse events leading to discontinuation. Most adverse events in the rituximab arm were mild or moderate in intensity. No patients in the rituximab arm had fatal adverse events.
The most commonly reported events considered as ADRs were infusion-related reactions and infections.
In a long-term observational safety study, 97 GPA/MPA patients received treatment with rituximab (mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician's standard practice and discretion. The overall safety profile was consistent with the well-established safety profile of rituximab in RA and GPA/MPA and no new adverse drug reactions were reported.
Description of selected adverse drug reactions: Infusion-related reactions: In the clinical trial conducted by innovator studying induction of remission with severe active GPA and MPA, IRRs 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. Of the 99 patients treated with rituximab, 12 (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. Rituximab was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.
In the maintenance therapy clinical trial, 7/57 (12%) patients in the rituximab arm experienced at least one infusion-related reaction. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (<4%). All IRR symptoms were mild or moderate and most of them were reported from the SOCs Respiratory, Thoracic and Mediastinal Disorders and Skin and Subcutaneous Tissue disorders.
Infections: In the clinical trial on induction of remission, which included 99 rituximab-treated 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 rituximab group was pneumonia at a frequency of 4%.
In the maintenance therapy clinical trial, 30/57 (53%) patients in the rituximab arm experienced infections. The incidence of all grade infections was similar between the arms. Infections were predominately mild to moderate. The most common infections in the rituximab arm included upper respiratory tract infections, gastroenteritis, urinary tract infections and herpes zoster. The incidence of serious infections was similar in both arms (approximately 12%). The most commonly reported serious infection in the rituximab group was mild or moderate bronchitis.
Malignancies: In the clinical trial on induction of remission, the incidence of malignancy in rituximab 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 standardised incidence ratios, the incidence of malignancies appears to be similar to that previously reported in patients with ANCA-associated vasculitis.
Cardiovascular adverse reactions: In the clinical trial on induction of remission, 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 Precautions).
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 rituximab 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 rituximab. The rate of overall infections and serious infections was not increased after the development of low IgA, IgG or IgM.
In the induction of remission clinical trial, at 6 months, in the rituximab 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.
In the maintenance therapy clinical trial, no clinically meaningful differences between the two treatment arms or decreases in total immunoglobulin, IgG, IgM or IgA levels were observed throughout the trial.
Neutropenia: In the induction of remission clinical trial, 24% of patients in the rituximab 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 rituximab-treated patients.
In the maintenance therapy clinical trial, the incidence of all-grade neutropenia was 0% for Rituximab-treated patients vs 5% for azathioprine treated patients.
Skin and subcutaneous tissue disorders: Toxic Epidermal Necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
Experience from pemphigus vulgaris: Summary of the safety profile: The safety profile of rituximab in combination with short-term, low-dose glucocorticoids in the treatment of patients with pemphigus vulgaris was studied in an innovator's Phase 3, randomised, controlled, multicenter, open-label study in pemphigus patients that included 38 pemphigus vulgaris (PV) patients randomised to the Rituximab group. Patients randomised to the Rituximab group received an initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15. Maintenance doses of 500 mg IV were administered at months 12 and 18. Patients could receive 1000 mg IV at the time of relapse (see Pharmacology: Pharmacodynamics under Actions).
The safety profile of Rituximab in patients with PV was consistent with that observed in RA and GPA/MPA patients.
Tabulated list of adverse reactions: Adverse drug reactions presented in Table 4 were adverse events which occurred at a rate of ≥5% among Rituximab-treated PV patients, with a ≥ 2% absolute difference in incidence between the Rituximab-treated group and the standard-dose prednisone group up to month 24. No patients were withdrawn due to ADRs. (See Table 4.)

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Description of selected adverse reactions: Infusion-related reactions: Infusion-related reactions in the pemphigus vulgaris clinical study were common (58%). Nearly all infusion-related reactions were mild to moderate. The proportion of patients experiencing an infusion-related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-related reactions. Symptoms of infusion-related reactions were similar in type and severity to those seen in RA and GPA/MPA patients.
Infections: Fourteen patients (37%) in the Rituximab group experienced treatment-related infections compared to 15 patients (42%) in the standard-dose prednisone group. The most common infections in the Rituximab group were herpes simplex and zoster infections, bronchitis, urinary tract infection, fungal infection and conjunctivitis. Three patients (8%) in the Rituximab group experienced a total of 5 serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, lung infection, Staphylococcal sepsis) and one patient (3%) in the standard-dose prednisone group experienced a serious infection (Pneumocystis jirovecii pneumonia).
Post-marketing experience: Non-Hodgkin's Lymphoma: The reporting frequencies in this section (rare, very rare) are based on estimated marketed exposures and largely data derived from spontaneous reports.
Additional cases of severe infusion-related reactions have been reported during post-marketing use of rituximab.
As part of the continuing post-marketing surveillance of rituximab safety, the following severe adverse reactions have been observed: Cardiovascular system: Severe cardiac events, including heart failure and myocardial infarction have been observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and mostly associated with infusion related reactions. Vasculitis, predominantly cutaneous, such as leukocytoclastic vasculitis, has been reported very rarely.
Respiratory system: Respiratory failure/insufficiency, pulmonary infiltrates in the context of infusion related reactions. Pulmonary infiltrates outside of infusion related reactions and intestinal pneumonitis have been reported rarely.
Skin and Appendages: Severe bullous skin reactions including fatal cases of toxic epidermal necrolysis have been reported rarely.
Nervous system: Cases of cranial neuropathy with or without peripheral neuropathy have been reported rarely. Signs and symptoms of cranial neuropathy, such as severe vision loss, hearing loss, loss of other senses, facial nerve palsy occurred at various times up to several months after completion of rituximab therapy.
Body as a whole: Serum-sickness like reactions have been reported rarely.
Infections and infestations: Cases of Hepatitis-B reactivation have been reported, the majority of which were in subjects receiving rituximab in combination with cytotoxic chemotherapy.
Other serious viral infections, either new, reactivation or exacerbation, some of which were fatal, have been reported with rituximab treatment. The majority of the patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Examples of these serious viral infections are infection caused by the herpes viruses (cytomegalovirus (CMV), Varicella zoster virus and Herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy (PML) and Hepatitis C virus.
Progression of Kaposi's sarcoma has been observed in rituximab-exposed patients with pre existing Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of the patients were HIV positive.
Gastrointestinal system: Gastro intestinal perforation, in some cases leading to death, has been observed in patients receiving rituximab in combination with chemotherapy or non-Hodgkin's lymphoma.
Laboratory Abnormalities: Non-Hodgkin's Lymphoma: Blood and lymphatic system: Neutropenia: Rarely the onset of neutropenia has occurred more than four weeks after the last infusion of rituximab.

Currently, there are limited data on possible drug interactions with rituximab.
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.
Renal toxicity has occurred in patients who experience tumor lysis syndrome (TLS) and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituximab is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue Rituximab in patients with a rising serum creatinine or oliguria.
Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.

Incompatibilities: No incompatibilities between rituximab and polyvinyl chloride or polyethylene bags or infusion sets have been observed.
Special precautions for disposal: Rituximab (Redditux) is provided in sterile, preservative-free, non-pyrogenic, single use vials.
Aseptically withdraw the necessary amount of Rituximab (Redditux), 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 discoloration prior to administration.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store vials in a refrigerator (2-8°C).
Keep the vial in the carton in order to protect from light.
Do not freeze.
Shelf life: 36 months.
The prepared infusion solution of Rituximab (Redditux) in 0.9% sodium chloride solution is physically and chemically stable for 24 hours at 2-8°C and subsequently 12 hours at room temperature (25°C). The prepared infusion solution of Rituximab (Redditux) in 5% D-glucose solution is physically and chemically stable for 24 hours at 2°C-8°C and subsequently for a further 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 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Targeted Cancer Therapy

L01FA01 - rituximab ; Belongs to the class of CD20 (Clusters of Differentiation 20) inhibitors. Used in the treatment of cancer.

Rx