Redditux

Redditux

rituximab

Manufacturer:

Dr. Reddy's

Distributor:

Zuellig Pharma

Marketer:

Dr. Reddy's
Full Prescribing Info
Contents
Rituximab.
Description
Each 10 mL and 50 mL vial contains Rituximab (r-DNA origin) 100 mg and 500 mg, respectively.
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/Inactive Ingredients: Sodium citrate, Polysorbate 80, Sodium chloride, Water for injection.
Action
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 rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg rituximab separated by a 14 day interval. Peripheral blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the majority of patients by week 40, whether rituximab was administered as monotherapy or in combination with methotrexate. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of rituximab.
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 Cmax 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 Cmax 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 Cmax (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).
Rheumatoid arthritis: Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 l/day (range, 0.091 to 0.67 l/day), and mean steady-state distribution volume was 4.6 l (range, 1.7 to 7.51 l).
Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 l/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSA and gender were the most significant covariates to explain inter-individual variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume of distribution and a faster clearance than female subjects. The gender-related pharmacokinetic differences are not considered to be clinically relevant and dose adjustment is not required. No pharmacokinetic data are available in patients with hepatic or renal impairment.
The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first infusion ranged from 157 to 171 μg /ml for 2 x 500 mg dose and ranged from 298 to 341 μg /ml for 2 x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 μg /ml for the 2 x 500 mg dose and ranged from 355 to 404 μg /ml for the 2 x 1000 mg dose. Mean terminal elimination half-life ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days for the 2 x 1000 mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared to the first infusion for both doses. The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was 170 to 175 μg /ml for 2 x 500 mg dose and 317 to 370 μg /ml for 2 x 1000 mg dose. Cmax following second infusion was 207 μg /ml for the 2 x 500 mg dose and ranged from 377 to 386 μg /ml for the 2 x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose. PK parameters for rituximab were comparable over the two treatment courses. The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following the same dosage regimen (2 x 1000 mg, iv, 2 weeks apart), were similar with a mean maximum serum concentration of 369 μg /ml and a mean terminal half-life of 19.2 days.
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.
Indications/Uses
Non-Hodgkin's lymphoma (NHL): REDDITUX is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.
REDDITUX maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
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.
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): 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.
Rheumatoid arthritis: REDDITUX is indicated, in combination with methotrexate, to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to one or more TNF antagonist therapies.
Redditux has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Dosage/Direction for Use
Redditux should only be administered under close supervision by an experienced medical person in a facility where immediate resuscitation measures are available.
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 REDDITUX.
In patients with non-Hodgkin's lymphoma and chronic lymphocytic leukaemia, premedication with glucocorticoids should be considered if Redditux is not given in combination with glucocorticoid containing chemotherapy.
In patients with rheumatoid arthritis, 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).
Posology: Follicular non-Hodgkin's lymphoma: Combination therapy: The recommended dose of 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.
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 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 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 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 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: 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 Redditux are recommended. When REDDITUX is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.
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 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.
Rheumatoid arthritis: A course of REDDITUX consists of two 1000 mg intravenous infusions. The recommended dosage of rituximab is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later.
The need for further courses should be evaluated 24 weeks following the previous course. Retreatment should be given at that time if residual disease activity remains, otherwise retreatment should be delayed until disease activity returns.
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.
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 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.
Rheumatoid arthritis only: Alternative subsequent, faster, infusion schedule: If patients did not experience a serious infusion related reaction with their first or subsequent infusions of a dose of 1000 mg rituximab administered over the standard infusion schedule, a more rapid infusion can be administered for second and subsequent infusions using the same concentration as in previous infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250mg/hour for the first 30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this infusion schedule can be used when administering subsequent infusions. Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion.
Overdosage
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.
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
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 rheumatoid arthritis: 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.
Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease.
Special Precautions
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 below. 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 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 rituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (described in the previous text). 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 outcome. 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. 69% 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.
Rheumatoid arthritis: Methotrexate (MTX) naïve populations with Rheumatoid arthritis: The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit risk relationship has not been established.
Infusion related reactions: Rituximab is associated with infusion related reactions (IRR), which may be related to release of cytokines and/or other chemical mediators. Premedication consisting of an analgesic/anti-pyretic drug and an anti-histaminic drug, should always be administered before each infusion of rituximab. In Rheumatoid arthritis premedication with glucocorticoids should also be administered before each infusion of rituximab in order to reduce the frequency and severity of infusion-related reactions. (see Adverse Reactions).
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 in the previous text).
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 rheumatoid arthritis and 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 rheumatoid arthritis.
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. In a randomized study, patients with RA treated with rituximab and methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after rituximab as compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst receiving rituximab therapy, these should be completed at least 4 weeks prior to commencing the next course of rituximab.
In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, the proportions of patients with positive antibody titers against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxic were generally similar to the proportions at baseline.
Concomitant/sequential use of other DMARDs: The concomitant use of rituximab and anti-rheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.
There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following rituximab (see Interactions). The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with rituximab, however patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following rituximab therapy.
Malignancy: Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience with rituximab in rheumatoid arthritis patients (see Adverse Reactions) a possible risk for the development of solid tumours cannot be excluded at this time, although present data do not seem to suggest any increased risk.
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.
Use In Pregnancy & Lactation
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.
Adverse Reactions
Experience from non-Hodgkin's lymphoma and chronic lymphocytic leukaemia: 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 Table 1. 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 "unknown". (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.
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.
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. In 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: Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituximab. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of Rituximab exposure. Discontinue Rituximab in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituximab to patients with severe mucocutaneous reactions has not been determined.
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 rheumatoid arthritis: The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.
The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) is summarized in the sections as follows.
Patients received 2 x 1000 mg of rituximab separated by an interval of two weeks; in addition to methotrexate (10-25 mg/week). Rituximab infusions were administered after an intravenous infusion of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days. Events are listed in Table 2 as follows. 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 <1/1,000) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most frequent adverse reaction considered due to receipt of rituximab were infusion related reactions. The overall incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during the initial course. In addition to adverse reactions seen in RA clinical trials for rituximab, progressive multifocal leukoencephalopathy (PML) (see Precautions) and serum sickness-like reaction have been reported during post marketing experience. (See Table 2.)

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Multiple Courses: Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs following first rituximab exposure was highest during the first 6 months and declined thereafter. This is mostly accounted for by infusion-related reactions (most frequent during the first treatment course), RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.
Infusion-related reactions: The most frequent ADRs following receipt of rituximab in clinical studies were IRRs (infusion related reactions, refer to Table 2). Among the 3189 patients treated with rituximab, 1135 (36%) experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to rituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials less than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs. Severe IRRs with fatal outcome have been reported in the post-marketing setting.
In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with rheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a serious IRR during or within 24 hours of their first studied infusion were allowed to receive a 2-hour intravenous infusion of rituximab. Patients with a history of a serious infusion reaction to a biologic therapy for RA were excluded from entry. The incidence, types and severity of IRRs were consistent with that observed historically. No serious IRRs were observed.
Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see Dosage & Administration and Precautions). Severe infusion-related reactions with fatal outcome with rituximab have been reported in the post-marketing setting.
Infections: The overall rate of infection was approximately 94 per 100 patient years in rituximab treated patients. The infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections and urinary tract infections. The incidence of infections that were serious or required IV antibiotic was approximately 4 per 100 patient years. The rate of serious infections did not show any significant increase following multiple courses of rituximab. Lower respiratory tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence in the rituximab arms compared to control arms.
Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported following use of rituximab for the treatment of autoimmune diseases. This includes Rheumatoid Arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and Vasculitis. In patients with non-Hodgkin's lymphoma receiving rituximab in combination with cytotoxic chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin's lymphoma). Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving rituximab (see Precautions).
Cardiovascular: Serious cardiac events were reported at a rate of 1.3 per 100 patient years in the rituximab treated patients compared to 1.3 per 100 patients years in placebo treated patients. The proportions of patients experiencing cardiac events (all or serious) did not increase over multiple courses.
Neutropenia: Events of neutropenia were observed with rituximab treatment, the majority of which were transient and mild or moderate in severity. Neutropenia can occur several months after the administration of rituximab (see Precautions).
In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and 0.27% (2/731) of placebo patients developed severe neutropenia.
Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported in the post-marketing setting, some of which were associated with fatal infections.
Skin and subcutaneous tissue disorders: Toxic Epidermal Necrolysis (Lyell's Syndrome) and Stevens-Johnson Syndrome, some with fatal outcome, have been reported very rarely.
Neurologic events: 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 recognised risk factors for PRES/RPLS, including the patients' underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.
Laboratory abnormalities: Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA patients treated with rituximab. There was no increased rate in overall infections or serious infections after the development of low IgG or IgM (see Precautions).
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.
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.
Gastro intestinal 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.
Rheumatoid Arthritis: The safety information collected during the post marketing experience reflects the expected adverse reaction profile as seen in clinical trials for rituximab in patients with Rheumatoid Arthritis.
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.
Drug Interactions
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 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.
Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in rheumatoid arthritis patients.
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.
In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic DMARD following rituximab. In these patients the rate of clinically relevant infection while on rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.
Caution For Usage
Special precautions for disposal: REDDITUX is provided in sterile, preservative-free, non-pyrogenic, single use vials.
Aseptically withdraw the necessary amount of 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.
Incompatibilities: No incompatibilities between rituximab and polyvinyl chloride or polyethylene bags or infusion sets have been observed.
Storage
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 Redditux is physically and chemically stable for 24 hours at 2-8°C and subsequently 12 hours at room temperature (25°C).
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.
ATC Classification
L01XC02 - rituximab ; Belongs to the class of monoclonal antibodies, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Soln for infusion (vial) (clear to opalescent, colourless to yellowish solution, essentially free of visible particles) 100 mg/10 mL x 1's. 500 mg/50 mL x 1's.
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