RITUXIVER ®
Rituximab
FORMULA:
Each 100 mg vial of Rituxiver® contains: Rituximab 100 mg (10 mg/ml). Excipients: polysorbate 80: sodium chloride, sodium citrate dehydrate, water for injection q.s. 10 ml.
Each 500 mg vial of Rituxiver® contains: Rituximab 500 mg (10 mg/ml). Excipients: polysorbate 80: sodium chloride, sodium citrate dehydrate, water for injection q.s. 50 ml.
THERAPEUTIC ACTION:
Antineoplastic agent, monoclonal antibody
INDICATIONS:
Non-Hodgkin Lymphoma (NHL)
In patients with stage III/IV follicular non-Hodgkin lymphoma who have not previously been treated, rituximab is indicated in combination with chemotherapy.
In patients with follicular lymphoma who have responded to induction treatment, rituximab is indicated for maintenance treatment.
In patients with stage III/IV follicular non-Hodgkin lymphoma who are chemo resistant or in their second or posterior relapse after chemotherapy, rituximab is indicated as monotherapy.
In patients with CD20-positive diffuse large B-cell non-Hodgkin lymphoma, rituximab is indicated in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone).
In patients with chronic lymphocytic leukemia (CLL) who have not been previously treated or who have relapsed or have been refractory to a previous treatment, rituximab is indicated in combination with chemotherapy. Evidence is limited on the efficacy and safety of treatment with rituximab in patients previously treated with monoclonal antibodies, including rituximab (whether alone or in combination with chemotherapy).
Rheumatoid arthritis (RA)
In adult patients with severe active rheumatoid arthritis who have presented inadequate response or intolerance to other disease-modifying antirheumatic drugs (DMARDs), including one or more treatments with tumor necrosis factor (TNF) inhibitors.
Rituximab in combination with methotrexate (MTX) is indicated for the treatment of rituximab has been shown to reduce the progression of joint damage measured by X-rays and to improve physical function when given in combination with methotrexate.
In adult patients with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA), rituximab is indicated in combination with glucocorticoids (MPA).
PHARMACOLOGICAL CHARACTERISTICS/PROPERTIES.
MECHANISM OF ACTION:
Rituximab is a mouse-human chimeric monoclonal antibody that specifically binds to the CD20 antigen.
This antigen is a phosphorylase transmembrane protein present in mature B lymphocytes and in pre-B cells expressed in more than 90% of all B-cell non-Hodgkin lymphomas (NHL). This antigen was not detected in stem cells, pro-B cells, normal plasma cells or in other normal tissues. This antigen does not internalize after antibody binding nor is it eliminated from the cell surface. CD20 does not circulate in plasma as a free antigen and, therefore, does not compete for antibody binding.
Rituximab is a mouse-human chimeric monoclonal antibody (mAb) with binding specificity to CD20, a phosphorylase transmembrane protein, which is located in pre-B cells and mature B lymphocytes (pan-B antigen restricted to B-cell lineage).
The antigen is found both in normal B-cells and in malignant B-cells (except myeloma cells and most of the precursor B-cells of acute lymphoblastic leukemia or ALL).
The Fab domain of rituximab binds to the CD20 antigen on the surface of B lymphocytes, while the Fc domain may recruit immune response effectors to mediate B-cell lysis. The possible mechanisms of effector-mediated cell lysis include complement dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). It has also been demonstrated that when rituximab binds to the CD20 antigen of B lymphocytes this induces cell death by apoptosis.
After the first rituximab dose in patients with hematological neoplasms or the second infusion in patients with rheumatoid arthritis or Wegener’s granulomatosis and microscopic polyangiitis, a decrease is observed in the peripheral B-cell count. Recovery starts after 6 months of treatment and evidence of repopulation is observed in most patients by week 40, regardless of whether it is given in monotherapy or in combination with methotrexate.
MODE OF ADMINISTRATION:
Rituxiver is a concentrated solution that must be diluted prior to intravenous administration. It must not be administered as pulse therapy or intravenous (IV) bolus.
Rituxiver infusions must be performed under the strict supervision of an expert physician and in an environment that has immediate access to complete resuscitation equipment.
Before every infusion, premedicate with an antipyretic and an antihistamine such as paracetamol and diphenhydramine.
In patients with rheumatoid arthritis, administer methylprednisolone or an equivalent corticosteroid 30 minutes prior to the infusion to reduce the frequency and severity of infusion-related reactions.
Premedication with glucocorticoids must be considered if rituximab is not going to be given in combination with chemotherapy that includes glucocorticoids for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia.
In patients with granulomatosis (WG) and with microscopic polyangiitis (MPA), administer glucocorticoids with rituximab.
In patients with chronic lymphocytic leukemia, consider prophylaxis for pneumonia due to Pneumocystis jiroveci and antiherpes drugs, and then after 12 months of treatment.
Also consider prophylaxis for pneumonia due to Pneumocystis jiroveci in patients with WG and MPA during rituximab treatment and then 6 months after the last infusion.
First infusion:
The initial recommended infusion rate is 50 mg/hour; after the first 30 minutes, in the absence of toxicity, this can be increased by 50 mg/hour, every 30 minutes, up to a maximum of 400 mg/hour.
Subsequent infusions:
Start the infusion at an initial speed of 100 mg/hour; in the absence of infusion toxicity this can be increased by 100 mg/hour every 30 minutes, up to a maximum of 400 mg/hour.
The prepared rituximab solutions must be administered as an intravenous infusion, using a specific catheter. Prepared solutions must not be administered in rapid infusion or IV bolus.
Patients must be strictly monitored to detect the onset of cytokine-release syndrome (see Precautions and warnings). The infusion must be immediately discontinued in patients who show evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia. In patients with non-Hodgkin lymphoma, evidence of tumor lysis syndrome must be subsequently evaluated through suitable laboratory tests, and evidence of pulmonary infiltration by chest X-ray. The infusion should not be restarted in any patient until complete remission of all symptoms and normalization of laboratory values and chest X-ray results. At that point on, the infusion may be restarted; initially the maximum rate is half the rate of the previous infusion. If the same severe adverse reactions were to occur a second time, the decision to terminate treatment should be seriously considered on a case-by-case basis. Mild or moderate reactions related to the infusion (see adverse reactions) are generally resolved by reducing the infusion rate. The infusion rate may be increased when symptoms improve.
Instructions to prepare the dilution:
Rituxiver® is dispensed in single-dose, apyrogenic, sterile, preservative-free vials.
Each milliliter of concentrated Rituxiver® solution contains 10 milligrams of rituximab.
Use aseptic techniques and disposable sterile materials when preparing the dilution.
Calculate and extract the necessary quantity of Rituxiver®, and dilute it in an infusion bag containing an aqueous solution for injection of sodium chloride 9 mg/ml (0.9%) or an aqueous solution for injection of 5% D-glucose up to a calculated rituximab concentration of 1 to 4 mg/ml. To mix and homogenize the diluted Rituxiver® solution, gently invert the bag to prevent foam from forming; perform this mixing process several times until the diluted rituximab solution is visually homogenous.
The diluted solution prepared for intravenous infusion must be used immediately.
Special precautions for storage, disposal and other handling:
Take care to ensure the sterility of the prepared solutions. The medicine does not contain any antimicrobial preservatives or bacteriostatic agents and, therefore, aseptic techniques must be maintained. Before administration, parenteral medicines must always be visually inspected to see if they contain particles or present alterations in color.
From a microbiological standpoint, the diluted solution prepared for intravenous infusion must be used immediately.
If it is not used immediately, the storage time and preservation until use and the conditions before use will be the responsibility of the user and must not exceed 24 hours, refrigerating it between 2°C and 8°C, and it must only be used if the dilution was performed under controlled and validated aseptic conditions.
Once the amount of dilution to be used has been extracted, the remaining concentrated Rituxiver solution must also be discarded, from a microbiological standpoint. It is the user’s responsibility to ensure that the extraction was performed observing strict aseptic conditions to be able to preserve it under the specified conditions (See Storage and preservation) for the next use.
Any unused medicine or waste material in contact with it should be disposed of in accordance with local requirements.
This medicine must not be used after the expiry date stated on the container.
This medicine must be used exclusively under prescription and medical supervision and cannot be repeated without a new medical prescription.
DOSING:
Dose adjustment during treatment
When rituximab is administered in combination with chemotherapy and the dose of the latter needs to be reduced, standard dose reductions must be applied, but reductions in the dose of rituximab are not recommended.
Follicular non-Hodgkin lymphoma. The suggested dose is 375 mg/m2 body surface, according to the following schedule:
a. COMBINED THERAPY:
Induction: in patients with follicular lymphoma who have not been previously treated, or in relapsed or refractory patients, induction is suggested with 375 mg/m2 body surface of rituximab per cycle, up to 8 cycles, in combination with chemotherapy.
Rituximab must be administered on day 1 of each cycle of chemotherapy, after administration of the glucocorticoid associated with the chemotherapy, if applicable.
Maintenance therapy for those who responded to induction:
In patients with follicular non-Hodgkin lymphoma who have not been previously treated and who have responded to the rituximab induction phase a schedule of 375 mg/m2 body surface is suggested, once every two months (2 months after the last dose of induction therapy) until disease progression or for up to a maximum period of 2 years.
In patients with relapsed or refractory follicular non-Hodgkin lymphoma: The recommended dose of rituximab, 2 months after the last induction dose, is 375 mg/m2 body surface once every 3 months until disease progression or for up to a maximum period of 2 years.
b. MONOTHERAPY:
In adult stage III/IV relapsed or refractory follicular lymphoma patients the recommended dose of rituximab used as monotherapy is 375 mg/m2 body surface administered as an IV infusion once a week for four weeks. In patients who have responded to previous rituximab treatment the suggested dose is the same as above, i.e. 375 mg/m2 body surface administered as an IV infusion once a week for four weeks.
Diffuse large B-cell non-Hodgkin lymphoma.
The suggested dose is 375 mg/m2 body surface, according to the following schedule:
Rituximab must be used in combination with CHOP chemotherapy. The recommended posology is 375 mg/m2 on the first day of each chemotherapy cycle, for eight cycles, after IV infusion of the glucocorticoid component of CHOP. The safety and efficacy has not been established for the combination of rituximab with other chemotherapies in diffuse large B-cell non-Hodgkin lymphoma.
Chronic Lymphocytic Leukemia (CLL):
The suggested dose is 375 mg/m2 prior to the start of chemotherapy and then 500 mg/m2 on day 1 of cycles 2 to 6.
In patients with CLL prophylaxis is recommended with suitable hydration and administration of uricostatic drugs 48 hours before the start of therapy to decrease the risk of tumor lysis syndrome.
For all patients with CLL whose lymphocyte count is > 25 x 10 9/l it is recommended that 100 mg of intravenous prednisone/prednisolone should be administered just before the rituximab infusion to decrease the risk and severity of acute infusion reactions and/or cytokine release syndrome.
The recommended rituximab dose in combination with chemotherapy for patients not previously treated or relapsed or refractory to a previous treatment is 375 mg/m2 body surface administered on day 0 of the first treatment cycle followed by 500 mg/m2 body surface on day 1 of the following cycles for 6 cycles in total. Chemotherapy must be administered after the rituximab infusion.
Rheumatoid Arthritis
Patients treated with rituximab must receive information about the risk of developing progressive multifocal leukoencephalopathy (see Precautions and warnings).
Patients must have received treatment with 100 mg of intravenous methylprednisolone 30 minutes before the rituximab infusion to reduce the incidence and severity of infusion-related reactions. Premedication must always be administered
Before each rituximab infusion; this consists of an analgesic/antipyretic (e.g. paracetamol and an antihistamine such as diphenhydramine).
For this indication, each rituximab cycle is composed of two 1000 mg intravenous infusions, separated by two weeks. That is, an IV infusion with 1000 mg of rituximab is suggested, and two weeks later the second dose is administered.
If a subsequent dose is required, this should not be given before 16 weeks, and preferably 24 weeks after the previous cycle.
Wegener's Granulomatosis (WG) and Microscopic Polyangiitis (MPA):
The suggested dose is 375 mg/m2 body surface once a week for 4 weeks. The recommended rituximab dose for the treatment of Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) is 375 mg/m2 body surface in IV infusion once a week for 4 weeks.
To treat severe vasculitis symptoms, methylprednisolone should be administered at a dose of 1000 mg/day IV for 1 to 3 days, followed by oral prednisone 1 mg/kg/day (without exceeding 80 mg/day), progressively reducing the dose as soon as possible according to clinical status within the 14 days prior to start of rituximab. It may be continued during and after the 4-week rituximab treatment cycle.
The safety and efficacy of treatment with subsequent rituximab cycles has not yet been established.
For patients with Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) prevention of pneumonia due to Pneumocystis jiroveci (PCP) is recommended during treatment and for at least 6 months following the last rituximab infusion.
Special populations
Pediatric population
The safety and efficacy of rituximab has not yet been established in children.
Elderly patients
No dose adjustment is required in elderly patients (> 65 years).
CONTRAINDICATIONS:
Hypersensitivity to the active substance or to any of its excipients or to mouse proteins.
Contraindications for use in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukaemia
Hypersensitivity to the active substance or to any of its excipients or to mouse proteins.
Serious active infections (see Precautions and warnings).
Patients in a seriously immunocompromised state.
Contraindications for use in Rheumatoid Arthritis
Hypersensitivity to the active substance or to any of its excipients or to mouse proteins.
Serious active infections (see Precautions and warnings).
Patients in a seriously immunocompromised state.
Severe heart failure (New York Heart Association class IV) or serious uncontrolled heart disease (see Precautions and warnings).
PRECAUTIONS AND WARNINGS:
Progressive Multifocal Leukoencephalopathy (PML):
All patients treated with rituximab must receive information to alert them to the potential risk of infections, including progressive multifocal leukoencephalopathy. This situation must be considered and evaluated and, if confirmed, rituximab treatment must be suspended.
The use of rituximab may be associated with a greater risk of PML. Patients must be monitored at regular intervals to detect any new neurological sign or symptom or any worsening that may suggest PML.
If the patient is suspected to have PML, rituximab administration must be suspended until this possibility has been ruled out. The physician must evaluate patients to determine whether the symptoms are indicative of neurological alteration and in such case, if these symptoms are indicative of PML, consider consultation with a neurologist.
In addition to evaluation, consider performing magnetic resonance imaging, preferably with contrast medium; CSF analysis to detect JC virus DNA; and repeat neurological evaluations.
The physician must be especially attentive to indicative symptoms of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). The patient must be advised to inform their partner or caregiver about their treatment, as these people may detect symptoms of which the patient is not aware. If the patient develops PML, treatment with rituximab must be permanently suspended and consider discontinuing any concurrent chemotherapy or immunosuppressant therapy.
Stabilization or improvement of the clinical outcome has been observed in immunocompromised patients with PML after immune system reconstitution. It is unknown whether early PML detection and discontinuation of rituximab treatment can lead to a similar stabilization or to an improvement in clinical outcome.
Infusion reactions:
Extreme precautions must be taken during treatment in patients who have a greater risk of developing severe cytokine-release syndrome. Infusion reactions caused by rituximab may be severe and even fatal. Severe reactions generally occur during the first infusion after 30 to 120 minutes; they include urticaria, hypotension, angioedema, bronchospasm, pulmonary infiltrates, respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactic events or death. The patients at risk are those with a large tumor mass or with a high number of circulating tumor cells (≥ 25,000/mm3), such as patients with chronic lymphocytic leukemia (CLL) and patients with pre-existing lung or heart conditions. Premedicate with paracetamol and antihistamines. RA with glucocorticoids. These patients must be closely monitored during the first infusion, and consider reducing the rate of the first infusion or fractioning the dose over more than two days in the first cycle and some subsequent cycles if the lymphocyte count is still high. If necessary, establish required medical treatment (e.g. glucocorticoids, epinephrine, bronchodilators or oxygen).
Severe cytokine release syndrome is characterized by severe dyspnea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, stiffness, urticarial and angioedema.
This syndrome may be associated with some characteristics of tumor lysis syndrome such as hyperuricemia, hyperkaliemia, hypocalcaemia, hyperphosphatasemia, acute renal failure and lactate dehydrogenase (LDH) elevation, and it may be associated with acute respiratory failure and death. Acute respiratory failure may be accompanied by interstitial infiltration or pulmonary edema, visible on a chest X-ray.
The syndrome frequently manifests within the first or second hour after starting the first infusion. Patients with a history of pulmonary failure or pulmonary tumor infiltration may have an increased risk of poor prognosis and extra precautions must be taken during their treatment. In patients who develop severe cytokine release syndrome (see Posology and methods of administration) the infusion must be discontinued immediately and they must receive intensive symptomatic treatment. The following is suggested: suitably hydrate (IV), administer antipruriginous agents and closely monitor renal function.
Given that the initial improvement of clinical symptoms may follow a relapse, these patients must be closely monitored until tumor lysis syndrome and pulmonary infiltration have been resolved or ruled out. Once the signs and symptoms have completely resolved, cytokine release syndrome rarely repeats in subsequent treatments.
Infusion-related adverse reactions 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 generally reversible after discontinuation of the rituximab infusion and administration of an antipyretic, an antihistamine and, occasionally, oxygen, intravenous saline solution or bronchodilators and, if necessary, glucocorticoids. For severe reactions see “Cytokine release syndrome”.
Cases of hypersensitivity reactions have been reported, including anaphylactic relations, after intravenous protein administration. Unlike cytokine release syndrome, true hypersensitivity reactions typically present during the first few minutes of the infusion. It is best to have medicines used to fight hypersensitivity reactions, i.e. adrenaline, antihistamines and glucocorticoids, available for immediate use in case an allergic reaction occurs during rituximab administration. Clinical manifestations of anaphylaxis may be similar to those previously described for cytokine release syndrome. Reactions attributable to hypersensitivity have been reported less frequently than those attributable to cytokine release. In addition to the reactions reported in some patients, there have been cases of myocardial infarction, pulmonary edema and acute reversible thrombocytopenia. Given that hypotension may occur during rituximab infusion, discontinuation of antihypertensive treatments may be considered 12 hours before the infusion.
Severe mucocutaneous reactions:
Patients treated with rituximab may present mucocutaneous reactions, which in some cases may have a fatal outcome. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis and toxic epidermal necrolysis.
These reactions have had a variable onset that includes reports with onset on the first day of exposure to the drug. This medicine should be discontinued in patients who experience severe mucocutaneous reactions. The safety of re-administration to patients who have experienced these types of events has not been determined.
Reactivation of hepatitis B virus:
In patients treated with drugs from the CD20-directed cytolytic antibodies group, such as rituximab, hepatitis B virus may sometimes be reactivated, resulting in fulminant hepatitis, liver failure and death. Cases were reported in patients with positive surface antigen (HBsAg+) and also in patients with negative surface antigen (HBsAg-) but positive for anti-core antibody (anti HBc+). Reactivation also occurred in patients whose hepatitis B infection seemed not to have been resolved (e.g. negative surface antigen, positive anti-core and positive anti-HBs antibodies).
Reactivation is defined as a sudden increase in hepatitis B virus replication manifested by a rapid increase in the level of serum HBV DNA or HBsAg detection in a person with previously negative HBsAg and positive anti-core (anti-HBc+). Virus reactivation is often followed by hepatitis, i.e. an increase in transaminase levels. In certain severe cases an increase in bilirubin levels, impaired liver function and death may occur.
Before starting treatment with rituximab, evaluate hepatitis B infection in all patients, requesting HBsAg and anti-HBc. In patients with evidence of prior infection (positive HBsAg, beyond antibody level or negative HBsAg but with positive anti-HBc) request consultation with an infectious disease specialist, hepatologist or expert physician for case follow-up and assessment of antiviral therapy before or during treatment with rituximab. For patients with current or previous evidence of hepatitis B infection, they must be monitored clinically and with laboratory tests to detect virus reactivation during rituximab treatment and for several months afterward. Cases of reactivation have been reported up to 24 months after completing treatment with rituximab.
In patients who develop virus reactivation while on treatment with rituximab, immediately discontinue the treatment and any concomitant chemotherapy and establish suitable treatment. There is not enough data on the safety of restarting treatment with rituximab in patients who had HBV reactivation; this should be discussed among doctors with experience in hepatitis B management once the reactivation has been resolved.
Cardiac disorders:
Cases of angina pectoris, cardiac arrhythmias such as atrial fibrillation and flutter, heart failure and/or myocardial infarction have been reported in patients treated with rituximab. Therefore, patients with a history of heart disease and/or cardiotoxicity associated with chemotherapy must be monitored closely.
Hematological toxicity:
Complete blood counts must be performed regularly before each cycle during rituximab treatment, including neutrophils and platelets. For combined treatment with chemotherapy, obtain a complete blood count weekly to monthly, and more often in patients who develop cytopenia. Although rituximab with monotherapy does not have a myelosuppressive effect, caution is advised before applying the treatment to patients with a neutrophil count of < 1.5 x 10 9/l and/or platelets < 75 x 10 9/l, given that clinical experience in this population is limited.
Rituximab has been used in patients undergoing autologous bone marrow transplantation and in other risk groups with presumably reduced bone marrow function without inducing myotoxicity.
Complete blood counts must be performed regularly during rituximab treatment, including neutrophils and platelets.
Infections:
During rituximab treatment, or after it has been completed, severe and even fatal bacterial or fungal infections may occur, and viral infections may even appear or be reactivated; these were reported in patients with hypogammaglobulinaemia. The infections reported included cytomegalovirus, herpes simplex, parvovirus B19, varicella zoster, West Nile virus and hepatitis B. Discontinue the product in serious infections and establish suitable anti-infectious treatment.
Rituximab must not be given to patients with severe active infections (e.g. tuberculosis, sepsis and opportunistic infections, see Contraindications). The physician must take special care when considering the use of rituximab in patients with a history of chronic or recurring infections, or in underlying conditions that may cause a greater predisposition to infections (see adverse reactions).
Rituximab treatment must not be initiated in patients with severe active infections.
Cases of hepatitis B reactivation have been reported in patients treated with rituximab, including cases of fulminant hepatitis leading to death.
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during the post-marketing use of rituximab. Most of the patients had received this monoclonal antibody in combination with chemotherapy or as part of a stem cell transplant.
In patients with NHL and CLL the safety of immunization with live virus vaccines has not been studied after receiving treatment with rituximab; therefore, live virus vaccination is not recommended.
Patients treated with rituximab may receive inactivated vaccines; however, response percentages may be lower with inactivated vaccines.
Immunizations: the vaccination status of patients must be examined and current vaccination guidelines must be followed before rituximab treatment. In patients with RA, vaccination must have been completed at least 4 weeks before starting treatment with rituximab.
The safety of immunization with live virus vaccines after receiving rituximab treatment has not been studied. Therefore, live virus vaccine vaccination is not recommended during treatment with rituximab or while there is peripheral B-cell depletion. Patients with RA treated with rituximab may receive inactivated vaccines; however, response percentages may be lower with inactivated vaccines.
Intestinal obstruction and perforation:
Abdominal pain, intestinal obstruction and perforation sometimes leading to death may occur in patients on rituximab treatment in combination with chemotherapy. Perform a thorough evaluation of any patient who complains of abdominal pain.
Renal toxicity:
Severe or even fatal renal toxicity may occur after the administration of rituximab in patients with NHL; this was seen in patients with tumor lysis syndrome and in patients with NHL on combined treatment with cisplatin. This combination is not recommended. Closely monitor for signs of renal failure and discontinue rituximab therapy in the case of increased creatinine or oliguria.
Rheumatoid arthritis, Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA)
Rituximab is not recommended in populations with rheumatoid arthritis who have not been previously treated with methotrexate (MTX), as a favorable risk/benefit ratio has not been established.
Concomitant/sequential use with other disease-modifying antirheumatic drugs (DMARDs):
Concomitant use of rituximab and other antirheumatic treatments other than those included in the indication and posology of rheumatoid arthritis is not recommended.
There is limited data in clinical trials to completely assess the safety of sequential use of other DMARDs (including TNF and other biological inhibitors) after rituximab therapy (see Interactions). The available data suggest that the incidence of clinically relevant infection does not change when these therapies are used in patients previously treated with rituximab; however, patients must be closely monitored for signs of infection if biological agents or DMARDs are used after rituximab treatment.
When there is peripheral B-cell depletion after rituximab treatment, concomitant administration of immunosuppressant that are not corticosteroids has not yet been studied in patients with Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA).
Malignant neoplasms:
Immunomodulating drugs may increase the risk of malignant neoplasms. Based on the limited experience with rituximab in patients with rheumatoid arthritis (see Adverse reactions), the existing data do not seem to suggest an increase in the risk of malignant neoplasms. Nonetheless, a possible risk of developing solid tumors cannot be excluded at this time.
In patients with Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA), complete blood counts and platelet counts must be performed at 2- to 4-month intervals during rituximab treatment. Rituximab-induced cytopenia may last for months beyond the treatment period.
Re-treatment of patients with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA):
There are limited data on the safety and efficacy of rituximab in subsequent cycles (see Posology and forms of administration).
Effects on the ability to drive and use machines:
Although studies on the ability to drive and use machines have not been conducted for rituximab, the pharmacological activity and adverse reactions reported to date do not suggest that such effects would be probable.
Fertility pregnancy and breast-feeding:
Fertility / Pregnancy: It is known that immunoglobulin G (IgG) crosses the placental barrier. Lymphocyte B levels have not been determined in the newborns of mothers exposed to rituximab in clinical trials. There is not sufficient controlled data in pregnant women; however, temporary B-cell depletion and lymphocytopenia have been reported in some children born to mothers exposed to rituximab during pregnancy. Therefore, rituximab should not be administered to a pregnant woman unless the expected benefit outweighs the potential risk.
During and for up to 12 months after treatment with rituximab, females of childbearing potential must use effective contraceptive methods due to the length of time that rituximab stays in the body in patients with B-cell depletion.
Breast-feeding: It is unknown whether rituximab is excreted in human milk. However, considering that IgG is excreted in human milk and that rituximab has been detected in the milk of lactating monkeys, women must not breast-feed their children during rituximab treatment or during the following 12 months.
INTERACTIONS:
There is currently limited data on possible drug interactions with rituximab. In patients with CLL, concomitant administration of rituximab and fludarabine or cyclophosphamide does not seem to have effects on the pharmacokinetics of these drugs. Moreover, there is no apparent effect of fludarabine or cyclophosphamide on the pharmacokinetics of rituximab. Co-administration with methotrexate does not modify the pharmacokinetics of rituximab in patients with rheumatoid arthritis. Patients with titers of human ant murine antibody/human antichimeric antibody (HAMA/HACA) may suffer from allergic reactions or hypersensitivity when treated with other therapeutic or diagnostic monoclonal antibodies. In patients with rheumatoid arthritis, 283 patients received a sequential treatment with a biological DMARD after rituximab. During rituximab treatment, the incidence of clinically relevant infections in these patients was 6.01 per 100 patient-years compared to 4.97 per 100 patient-years after treatment with the biological DMARD.
ADVERSE REACTIONS:
Experience in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia
Adverse reactions to the medicine observed with greater frequency were those reactions related to the infusion that occurred during the first infusion in most patients. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and was less than 1% after 8 doses of rituximab. During clinical trials in patients with NHL, approximately 30-55% of patients experienced infections reactions (mostly bacterial and viral); in studies with CLL this figure was 30-50% of patients.
Serious adverse reactions to the medicine reported or observed with the greatest frequency were:
- Infusion-related reactions (including cytokine release syndrome and tumor lysis syndrome).
- Infections.
- Cardiovascular events.
- Other serious adverse reactions reported include hepatitis B reactivation and PML.
The adverse reactions listed below 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). Adverse reactions to the medicine identified only during post-marketing studies, the frequency of which cannot be estimated, are defined as “not known”.
Infections:
Very common: bacterial and viral infections, bronchitis.
Common: sepsis, pneumonia, febrile infection, herpes zoster, respiratory tract infection, fungal infection, infections of unknown etiology, acute bronchitis, sinusitis, hepatitis B.
Rare: serious viral infections.
Hematopoietic disorders:
Very common: neutropenia, leukopenia, febrile neutropenia, thrombocytopenia.
Common: anemia, pancytopenia, granulocytopenia.
Uncommon: clotting disorders, aplastic anemia, hemolytic anemia, and lymphadenopathy.
Very rare: temporary increase in IgM serum levels.
Not known: late-onset neutropenia.
Immune system disorders:
Very common: infusion-related reactions, angioedema.
Common: hypersensitivity.
Rare: anaphylaxis.
Very rare: tumor lysis syndrome, cytokine release syndrome.
Not known: severe infusion-related thrombocytopenia.
Metabolism and nutrition disorders:
Common: hyperglycemia, weight loss, peripheral edema, facial edema, increase in LDH, hypocalcaemia.
Rare: anaphylaxis.
Psychiatric disorders:
Uncommon: depression, nervousness.
Neurological disorders:
Common: paresthesia, hypoesthesia, agitation, insomnia, vasodilation, vertigo, anxiety.
Uncommon: dysgeusia.
Very rare: peripheral neuropathy with facial nerve paralysis.
Not known: cranial neuropathy, loss of other senses.
Eye and ear disorders:
Common: tearing, conjunctivitis, tinnitus, ear pain.
Very rare: serious vision loss.
Not known: hearing loss.
Cardiac disorders:
Common: myocardial infarction, arrhythmia, atrial fibrillation, tachycardia, cardiac disorders.
Uncommon: left ventricular failure, supraventricular tachycardia, ventricular tachycardia, angina, myocardial ischemia, and bradycardia.
Rare: severe cardiac events.
Very rare: heart failure.
Vascular disorders:
Common: hypertension, orthostatic hypotension, hypotension.
Very rare: vasculitis (mainly cutaneous), leukocytoclastic vasculitis.
Respiratory, thoracic and mediastinal disorders:
Common: bronchospasm, respiratory disease, chest pain, dyspnea, increase in cough, rhinitis.
Uncommon: asthma, obliterative bronchitis, lung alteration, hypoxia.
Rare: interstitial lung disease.
Very rare: respiratory failure.
Not known: pulmonary infiltration.
Gastrointestinal disorders:
Very common: nausea
Common: vomiting, diarrhea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia.
Uncommon: abdominal swelling.
Very rare: gastrointestinal perforation.
Skin and subcutaneous tissue disorders:
Very common: pruritus, rash, alopecia.
Common: urticaria, sweating, night sweats, skin disorders.
Very rare: severe bullous drug reactions, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders:
Common: hypertonia, myalgia, arthralgia, back pain, neck pain, pain.
Renal and urinary disorders:
Very rare: kidney failure.
General disorders and administration site conditions:
Very common: fever, chills.
Common: tumor pain, flushing, malaise, cold syndrome, fatigue, tremors, multiple organ failure.
Uncommon: pain at the infusion site.
Investigations:
Very common: low IgG levels.
Experience in Rheumatoid Arthritis
The adverse reactions listed below 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).
The most common adverse reactions and those considered to be attributable to rituximab administration were infusion reactions. The total incidence of infusion-related reactions in clinical trials was 23% in the first infusion and it decreased in successive infusions. Rituximab consisted of infusion reactions. The total incidence of infusion-related reactions in clinical trials was 23% in the first infusion and it decreased in successive infusions. Severe infusion-related reactions were uncommon (0.5% of patients) and occurred mostly in the first cycle. In addition to the adverse reactions observed in clinical trials, during the marketing of rituximab Progressive Multifocal Leukoencephalopathy (PML) (see precautions and warnings) and serum sickness-like reactions have been reported.
Infections:
Very common: upper respiratory tract infection, urinary tract infection.
Common: bronchitis, sinusitis, tinea pedis.
Very uncommon: PML, reactivation of hepatitis B virus.
Hematopoietic disorders:
Very uncommon: serum sickness-like reactions.
Cardiac disorders:
Rare: angina pectoris, atrial fibrillation, heart failure, myocardial infarction.
Very uncommon: atrial flutter.
Immune system disorders:
Very common: infusion-related reactions (hypertension, nausea, rash, fever, pruritus, urticaria, throat irritation, sensation of flushing, hypotension, rhinitis, stiffness, tachycardia, fatigue, oropharyngeal pain, peripheral edema, and erythema.
Uncommon: infusion-related reactions such as generalized edema, bronchospasm, wheezing, laryngeal edema, angioneurotic edema, generalized pruritus, anaphylaxis, anaphylactic reaction, hyperglycemia, weight loss, peripheral edema, facial edema, increase in LDH, hypocalcaemia.
Metabolism and nutrition disorders:
Common: hypercholesterolemia.
Nervous system disorders:
Very common: headache.
Common: paresthesia, migraine, dizziness, sciatica.
Skin and subcutaneous tissue disorders:
Common: alopecia.
Psychiatric disorders:
Common: depression, anxiety.
Gastrointestinal disorders:
Common: dyspepsia, diarrhea, gastroesophageal reflux, mouth ulcers, upper abdominal pain.
Musculoskeletal disorders:
Common: arthralgia/musculoskeletal pain, osteoarthritis, bursitis.
Laboratory abnormalities
Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) was observed in patients with rheumatoid arthritis treated with rituximab. No increase in the general infection or serious infection rate was observed after developing hypogammaglobulinaemia.
Experience in Wegener’s Granulomatosis and Microscopic Polyangiitis (MPA)
The following adverse reactions were observed in ≥10% of patients up to the 6th month in a clinical trial conducted in patients with Wegener’s granulomatosis and microscopic polyangiitis: infections, nausea, diarrhea, headache, muscle spasms, arthralgia, anemia, leukocytopenia, peripheral edema, fatigue, insomnia, increase in ALT, cough, epistaxis, dyspnea, hypertension, infusion-related reactions, and skin rashes.
Laboratory abnormalities
Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) was observed in these patients with WG and MPA treated with rituximab in clinical trials.
OVERDOSE:
There is no experience related to overdose in clinical trials. Single doses tested in patients with autoimmune diseases have not been single doses above 1000 mg.
After marketing, five cases of rituximab overdose were reported. In three of the cases no adverse reactions were reported. In the other two, adverse reactions with flu symptoms were reported with a dose of 1.8 g rituximab, and fatal respiratory failure with a dose of 2 g rituximab.
PRESENTATIONS:
Each box contains 1 vial of 100mg rituximab per 10 ml.
Each box contains 1 vial of 500mg rituximab per 50 ml.
CONDITIONS FOR PRESERVATION AND STORAGE:
Vials must be stored in a refrigerator between 2°C and 8°C.
Store vials in their original box and packaging to protect contents from light. Do not freeze or shake.
Keep out of the reach and sight of children.
Marketing Authorization Holder & Manufacturing site:
Actoverco Pharmaceutical Factory, Karaj – Iran
Telefax: +982634760314-15
Email: info@actoverco.com