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General: In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukaemia Patients: Infusion/administration-related reactions: MabThera/Rituxan is associated with infusion/administration-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.
Infusion-related reactions for MabThera/Rituxan IV: Severe infusion-related reactions (IRRs) with fatal outcome have been reported during post-marketing use. Severe IRRs usually manifested within 30 minutes to 2 hours after starting the first MabThera/Rituxan IV infusion, were characterized by pulmonary events and included, in some cases, rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see Adverse Reactions). Patients with a high tumour burden or with a high number (>25 x 109/L) of circulating malignant cells such as patients with CLL and mantle cell lymphoma may be at higher risk of developing severe IRRs. Infusion reaction symptoms are usually reversible with interruption of the infusion. Treatment of infusion-related symptoms with diphenhydramine and paracetamol/acetaminophen is recommended. Additional treatment with bronchodilators or IV saline may be indicated. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 100 mg/hour to 50 mg/hour) when symptoms have completely resolved. Most patients who have experienced non-life threatening IRRs have been able to complete the full course of MabThera/Rituxan IV therapy. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe IRRs.
Patients with a high number (>25 x 109/L) of circulating malignant cells or high tumour burden such as patients with CLL and mantle cell lymphoma who may be at higher risk of especially severe IRRs, 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.
Hypersensitivity reactions/Anaphylaxis: Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. Epinephrine, antihistamines and glucocorticoids should be available for immediate use in the event of a hypersensitivity reaction to MabThera/Rituxan IV.
Administration-related reactions for MabThera/Rituxan SC: Local cutaneous reactions, including injection site reactions, have been reported in patients receiving MabThera/Rituxan SC. Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see Adverse Reactions). Some local cutaneous reactions occurred more than 24 hours after the SC drug administration. The majority of local cutaneous reactions seen following administration of the SC formulation were mild or moderate and resolved without any specific treatment.
All patients must always receive their first dose of MabThera/Rituxan by intravenous administration in order to avoid an irreversible administration of the full MabThera/Rituxan SC dose during Cycle 1. During this cycle the patient would have the highest risk of experiencing an IRR that can be treated effectively by slowing or stopping the infusion. The subcutaneous formulation must only be given at the second or subsequent cycles. Patients unable to receive the full MabThera/Rituxan IV infusion dose should continue to receive subsequent cycles with MabThera/Rituxan IV until a full IV dose is successfully administered. For patients who are able to receive the full MabThera/Rituxan IV infusion dose the second or subsequent MabThera/Rituxan dose can be given subcutaneously using the MabThera/Rituxan SC formulation (see Dosage & Administration). As with the intravenous formulation, MabThera/Rituxan SC should be administered in an environment where full resuscitation facilities are immediately available and under the close supervision of a healthcare professional. Premedication consisting of an analgesic/antipyretic and an antihistamine should always be administered before each dose of MabThera/Rituxan SC. Premedication with glucocorticoids should also be considered.
Patients should be observed for at least 15 minutes following MabThera/Rituxan SC administration. A longer period may be appropriate in patients with an increased risk of hypersensitivity reactions.
Patients should be instructed to contact their treating physician immediately if symptoms that are suggestive of severe hypersensitivity reactions or cytokine release syndrome occur at any time after drug administration.
Pulmonary events: Pulmonary events have included hypoxia, lung infiltration, and acute respiratory failure. Some of these events have been preceded by severe bronchospasm and dyspnea. In some cases, symptoms worsened over time, while in others initial improvement was followed by clinical deterioration. Therefore, patients experiencing pulmonary events or other severe infusion-related symptoms should be closely monitored until complete resolution of their symptoms occurs. 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. Acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or edema, visible on a chest X-ray. The syndrome usually manifests itself within one or two hours of initiating the first infusion. Patients who experience severe pulmonary events should have their MabThera/Rituxan administration interrupted immediately (see Dosage & Administration) and should receive aggressive symptomatic treatment.
Rapid tumour lysis: MabThera/Rituxan mediates the rapid lysis of benign and malignant CD20-positive cells. Signs and symptoms (e.g., hyperuricemia, hyperkalemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated LDH) consistent with tumour lysis syndrome (TLS) have been reported to occur after the first MabThera/Rituxan IV infusion in patients with high numbers of circulating malignant lymphocytes. Prophylaxis for TLS should be considered for patients at risk of developing rapid tumour lysis (e.g., patients with a high tumour burden or with a high number [>25 x 109/L] of circulating malignant cells such as patients with CLL or mantle cell lymphoma). These patients should be followed closely and appropriate laboratory monitoring performed. Appropriate medical therapy should be provided for patients who develop signs and symptoms consistent with rapid tumour lysis. Following treatment and complete resolution of signs and symptoms, subsequent MabThera/Rituxan IV therapy has been administered in conjunction with prophylactic therapy for TLS in a limited number of cases.
Cardiovascular: Since hypotension may occur during MabThera/Rituxan administration consideration should be given to withholding antihypertensive medications 12 hours prior to and throughout MabThera/Rituxan IV/SC administration. Angina pectoris, cardiac arrhythmia, such as atrial flutter and fibrillation, heart failure or myocardial infarction have occurred in patients treated with MabThera/Rituxan IV/SC. Therefore patients with a history of cardiac disease should be monitored closely.
Monitoring of blood counts: Although MabThera/Rituxan is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophil counts of <1.5 x 109/L and/or platelet counts of <75 x 109/L, as clinical experience with such patients is limited. MabThera/Rituxan IV has been used in patients who underwent autologous bone marrow transplantation and in other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity.
Consideration should be given to the need for regular full blood counts, including platelet counts, during monotherapy with MabThera/Rituxan. When MabThera/Rituxan is given in combination with CHOP or CVP chemotherapy, regular full blood counts should be performed according to usual medical practice.
Infections: MabThera/Rituxan treatment should not be initiated in patients with severe active infections.
Hepatitis B infections: Cases of hepatitis B reactivation, including reports of fulminant hepatitis, some of which were fatal, have been reported in subjects receiving MabThera/Rituxan IV, although the majority of these subjects were also exposed to cytotoxic chemotherapy. The reports are confounded by both the underlying disease state and the cytotoxic chemotherapy.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera/Rituxan. 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 MabThera/Rituxan. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
Progressive multifocal leukoencephalopathy: Cases of progressive multifocal leukoencephalopathy (PML) have been reported during use of MabThera/Rituxan IV in NHL and CLL (see Post-Marketing under Adverse Reactions). The majority of patients had received MabThera/Rituxan IV in combination with chemotherapy or as part of a haematopoietic stem cell transplant. Physicians treating patients with NHL or CLL should consider PML in the differential diagnosis of patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Skin reactions: Severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see Post-Marketing under Adverse Reactions). In case of such an event with a suspected relationship to MabThera/Rituxan, treatment should be permanently discontinued.
Immunization: The safety of immunization with live viral vaccines following MabThera/Rituxan IV/SC therapy has not been studied and vaccination with live virus vaccines is not recommended.
Patients treated with MabThera/Rituxan 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 MabThera/Rituxan IV monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for >2-fold increase in antibody titer).
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 MabThera/Rituxan IV.
Rheumatoid Arthritis (RA), Granulomatosis with Polyangiitis (Wegener's) (GPA) and Microscopic Polyangiitis (MPA) Patients and Pemphigus Vulgaris (PV) Patients: The efficacy and safety of MabThera/Rituxan IV for the treatment of autoimmune diseases other than rheumatoid arthritis, granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis and pemphigus vulgaris have not been established.
Infusion-related reactions: MabThera/Rituxan IV is associated with infusion-related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators.
For RA patients, most infusion-related events reported in clinical trials were mild to moderate in severity. Severe IRRs with fatal outcome have been reported in the post-marketing setting (see Post-Marketing under Adverse Reactions). Closely monitor patients with pre existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions. The most common symptoms were 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 of any treatment course than following the second infusion. Subsequent MabThera/Rituxan IV infusions were better tolerated by patients than the initial infusion. Less than 1% of patients experienced serious IRRs, with most of these reported during the first infusion of the first course (see Adverse Reactions). The reactions reported were usually reversible with a reduction in rate or interruption of MabThera/Rituxan IV infusion, and administration of an anti-pyretic, an antihistamine and occasionally oxygen, intravenous saline, bronchodilators, or glucocorticoids as required. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue MabThera/Rituxan IV. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 100 mg/hour to 50 mg/hour) when symptoms have completely resolved.
Infusion-related reactions for GPA/MPA and PV patients were consistent with those seen for RA patients in clinical trials (see Adverse Reactions).
Hypersensitivity reactions/Anaphylaxis: Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. Medicinal products for the treatment of hypersensitivity reactions (e.g., epinephrine, antihistamines and glucocorticoids) should be available for immediate use in the event of an allergic reaction during administration of MabThera/Rituxan IV.
Cardiovascular: Since hypotension may occur during MabThera/Rituxan IV infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the MabThera/Rituxan infusion IV.
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure or myocardial infarction have occurred in patients treated with MabThera/Rituxan IV. Therefore, patients with a history of cardiac disease should be monitored closely (see Infusion-related reactions as previously mentioned).
Infections: Based on the mechanism of action of MabThera/Rituxan and the knowledge that B-cells play an important role in maintaining normal immune response, patients may have an increased risk of infection following MabThera/Rituxan IV therapy (see Pharmacology: Pharmacodynamics: Mechanism of Action under Actions). MabThera/Rituxan IV should not be administered to patients with an active infection or severely immunocompromised patients (e.g., where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of MabThera/Rituxan IV 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). Patients who develop infection following MabThera/Rituxan IV therapy should be promptly evaluated and treated appropriately.
Hepatitis B infections: Cases of hepatitis B reactivation including those with a fatal outcome have been reported in RA, GPA and MPA patients receiving MabThera/Rituxan IV.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera/Rituxan IV. 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 MabThera/Rituxan IV. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
Skin reactions: Severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see Post-Marketing under Adverse Reactions). In case of such an event with a suspected relationship to MabThera/Rituxan IV, treatment should be permanently discontinued.
Progressive multifocal leukoencephalopathy: Cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of MabThera/Rituxan IV for the treatment of autoimmune diseases including RA. Several, but not all of the reported cases had potential risk factors for PML, including the underlying disease, long-term immunosuppressive therapy or chemotherapy. PML has also been reported in patients with autoimmune disease not treated with MabThera/Rituxan IV. Physicians treating patients with autoimmune diseases should consider PML in the differential diagnosis of patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Immunization: The safety of immunization with live viral vaccines following MabThera/Rituxan IV therapy has not been studied. Therefore, vaccination with live virus vaccines is not recommended whilst receiving MabThera/Rituxan IV or whilst peripherally B-cell depleted. Patients treated with MabThera/Rituxan IV may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced.
For patients treated with MabThera/Rituxan IV, physicians should review the patient's vaccination status and patients should, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating MabThera/Rituxan IV therapy. Vaccinations should be completed at least 4 weeks prior to first administration of MabThera/Rituxan IV.
In a randomized study, patients with RA treated with MabThera/Rituxan IV 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 (34% vs. 80%), when given at least 6 months after MabThera/Rituxan IV as compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst receiving MabThera/Rituxan IV therapy, these should be completed at least 4 weeks prior to commencing the next course of MabThera/Rituxan IV.
In the overall experience of MabThera/Rituxan IV repeat treatment in RA patients over one year, the proportions of patients with positive antibody titers against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.
Methotrexate naïve RA populations: The use of MabThera/Rituxan IV is not recommended in methotrexate-naïve patients since a favourable benefit risk relationship has not been established.
Drug Abuse and Dependence: No data to report.
Effects on Ability to Drive or Use Machinery: MabThera/Rituxan has no or negligible effect on the ability to drive and use machines.
Renal Impairment: The safety and efficacy of renal impairment in MabThera/Rituxan patients has not been established.
Hepatic Impairment: The safety and efficacy of hepatic impairment in MabThera/Rituxan patients has not been established.
Females and Males of Reproductive Potential: MabThera/MabThera SC: Fertility: No preclinical fertility studies have been conducted.
Animal data: Developmental toxicity studies performed in cynomolgus monkeys revealed no evidence of embryotoxicity in utero. Newborn offspring of maternal animals exposed to MabThera/Rituxan were noted to have depleted B-cell populations during the post natal phase.
MabThera SC: Pharmacokinetic and toxicology studies in animals demonstrate reduction in foetal weight and increase in the number of resorptions following injection of rHuPH20 at maternal systemic exposure levels comparable to those that could occur after accidental bolus IV administration of a single vial of the MabThera/Rituxan SC formulation in humans, based on the most conservative assumptions possible (see Pharmacology: Toxicology: Preclinical Safety: MabThera SC under Actions).
Contraception: Women of childbearing age must employ effective contraceptive methods during and for 12 months after treatment with MabThera/Rituxan.
Use in Children: Pediatric Patients with Granulomatosis with Polyangiitis (Wegener's) (GPA) and Microscopic Polyangiitis (MPA): In a study, twenty-five pediatric patients (6 children ≥ 2 years to < 12 years and 19 adolescents ≥ 12 years to < 18 years) with active GPA/MPA were administered IV MabThera/Rituxan (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
In general, the adverse drug reactions observed in MabThera/Rituxan IV-treated pediatric patients with active GPA/MPA during the overall study period were consistent in type, nature and severity to those seen in adult patients (see Clinical Trials under Adverse Reactions).
The efficacy of MabThera/Rituxan IV in pediatric active GPA/MPA patients is based on PK exposure from WA25615 (PePRS) and extrapolation from the established efficacy of MabThera/Rituxan IV in adult GPA/MPA patients (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies and Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
The safety and efficacy of MabThera/Rituxan in pediatric patients has not been studied in disease other than GPA/MPA.
MabThera/Rituxan IV should not be used in pediatric patients with GPA/MPA < 2 years of age as there is a possibility of an inadequate immune response towards childhood vaccinations against common, vaccine preventable childhood diseases (e.g. measles, mumps, rubella, and poliomyelitis).
Hypogammaglobulinaemia has been observed in pediatric patients treated with MabThera/Rituxan IV, in some cases severe and requiring long-term immunoglobulin substitution therapy (see Clinical Trials under Adverse Reactions). The consequences of long term B-cell depletion in pediatric patients are unknown.
Use in the Elderly: The safety and efficacy of MabThera/Rituxan in geriatric patients has not been established.
