Rixathon Special Precautions

General: In order to improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded in the patient file.
Non-Hodgkin’s Lymphoma Patients and Chronic Lymphocytic Leukaemia Patients: Infusion/administration-related reactions: Rituximab 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.
This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions are described as follows.
Severe infusion-related reactions (IRRs) with fatal outcome have been reported during post-marketing use of the rituximab intravenous formulation. Severe IRRs usually manifested within 30 minutes to 2 hours after starting the first rituximab intravenous infusion. They 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 as follows and Adverse Reactions).
Severe cytokine release syndrome is characterised by severe dyspnoea, 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, hyperphosphataemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death.
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 infusion-related reactions. Infusion reaction symptoms are usually reversible with interruption of the infusion. Treatment of infusion-related symptoms with diphenhydramine and 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/h to 50 mg/h) when symptoms have completely resolved. Most patients who have experienced non-life threatening infusion-related reactions have been able to complete the full course of rituximab IV therapy. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe infusion-related reactions.
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 infusion-related reactions, should only be treated with extreme caution and when other therapeutic alternatives have been exhausted. 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. 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 a hypersensitivity reaction to rituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (as previously described). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.
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. See cytokine release syndrome as previously mentioned for severe reactions.
Pulmonary events: Pulmonary events have included hypoxia, pulmonary infiltrates, 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 infusion interrupted immediately (see Dosage & Administration) and should receive aggressive symptomatic treatment.
Rapid tumour lysis: Rituximab mediates the rapid lysis of benign and malignant CD20-positive cells. Signs and symptoms (e.g., hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphataemia, acute renal failure, elevated LDH) consistent with tumour lysis syndrome (TLS) have been reported to occur after the first rituximab 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 and 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 for and complete resolution of signs and symptoms, subsequent rituximab IV therapy has been administered in conjunction with prophylactic therapy for TLS in a limited number of cases.
Rituximab IV infusions should be administered in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced oncologist/hematologist.
Cardiovascular: Since hypotension may occur during rituximab administration, consideration should be given to withholding anti-hypertensive medicinal product 12 hours prior to and throughout RIXATHON infusion.
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.
Monitoring of blood counts: Although rituximab 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 < 75 x 10⁹/L as clinical experience in this population is limited. Rituximab 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 RIXATHON. When RIXATHON is given with CHOP or CVP chemotherapy, regular full blood counts should be performed according to usual medical practice.
Infections: Serious infections, including fatalities, can occur during therapy with rituximab. RIXATHON 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 RIXATHON 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).
Hepatitis B Infections: Cases of hepatitis B reactivation, some of which were fatal, including reports of fulminant hepatitis, have been reported in subjects receiving rituximab 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 RIXATHON. 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 RIXATHON. Reactivation of HBV infection is a well-known complication in patients with chronic hepatitis B, especially in those receiving cytotoxic or immunosuppressive therapy. In addition, hematological malignancies may be a risk factor for HBV reactivation. 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.
The following additional serious viral infections, either new, reactivated or exacerbated, have been identified in clinical studies or post-marketing reports. The majority of patients were profoundly immune-suppressed. These viral infections included JC virus [progressive multifocal leukoencephalopathy (PML)], cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus and hepatitis C. In some cases, the viral infections occurred up to one year following discontinuation of rituximab and have resulted in death.
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.
Progressive multifocal leukoencephalopathy: Use of Rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a Neurologist should be considered as clinically indicated.
If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.
The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g., cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.
If a patient develops PML, the dosing of RIXATHON must be permanently discontinued. Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of rituximab therapy may lead to similar stabilisation or improved outcome.
Skin reactions: Severe skin reactions such as Toxic Epidermal Necrolysis and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see Adverse Reactions). In case of such an event with a suspected relationship to rituximab, treatment should be permanently discontinued.
Immunization: The safety of immunization with live viral vaccines, following rituximab therapy has not been studied and vaccination with live virus vaccines is not recommended.
Patients treated with RIXATHON may receive non-live vaccinations. However, with non-live vaccines response rates may be reduced. In a non-randomised study, patients with relapsed low-grade NHL who received rituximab monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for > 2-fold increase in antibody titer).
Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with rituximab.
Rheumatoid Arthritis Patients: Infusion-related Reactions: Rituximab IV is associated with infusion-related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators. Premedication with IV glucocorticoid significantly reduced the incidence and severity of these events and should be administered prior to rituximab IV treatment (see Dosage & Administration and Adverse Reactions).
Most infusion events reported were mild to moderate in severity. 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 rituximab infusions were better tolerated by patients than the initial infusion. Fewer 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 rituximab infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, IV saline or bronchodilators, and glucocorticoids if required. 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.
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 rituximab IV.
Cardiovascular: Since hypotension may occur during rituximab IV infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the rituximab IV infusion.
Angina pectoris, or cardiac arrhythmias such as atrial flutter and fibrillation heart failure or myocardial infarction have occurred in patients with non-Hodgkin's lymphoma treated with rituximab IV. Therefore patients with a history of cardiac disease and/or those receiving cardiotoxic drug therapy should be monitored closely during infusions.
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 may have an increased risk of infection following rituximab therapy. Rituximab 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 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). Patients who develop infection following rituximab therapy should be promptly evaluated and treated appropriately.
In patients with non-Hodgkin’s Lymphoma receiving rituximab in combination with cytotoxic chemotherapy, very rare cases of hepatitis B reactivation have been reported (see as follows).
Hepatitis B Infections: Cases of hepatitis B reactivation including those with a fatal outcome, have been reported in RA patients receiving rituximab IV.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with rituximab 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 rituximab 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 Adverse Reactions). In case of such an event with a suspected relationship to rituximab IV, treatment should be permanently discontinued.
Progressive Multifocal Leukoencephalopathy: Cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of rituximab IV for the treatment of autoimmune diseases (including RA). Several, but not all of the reported cases had potential multiple 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 rituximab 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.
The efficacy and safety of rituximab for the treatment of autoimmune diseases other than rheumatoid arthritis has not been established.
Immunization: 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 rituximab IV therapy and follow local/national guidance for adult vaccination against infectious disease. Vaccinations should be completed at least 4 weeks prior to first administration of rituximab IV.
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 receiving 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 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 rituximab IV 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 IV.
In the overall experience of rituximab IV repeat treatment 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 (MTX) naïve populations: The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit risk relationship has not been established.
Concomitant/sequential use of other DMARDs: The concomitant use of rituximab and antirheumatic 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. 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 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.
Sodium: This medicinal product contains 2.3 mmol (52.6 mg) sodium per 10 mL vial. This medicinal product contains 11.5 mmol (263.2 mg) sodium per 50 mL vial. To be taken into consideration by patients on a controlled sodium diet.
Effects on ability to drive and use machines: Rituximab may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of rituximab (see Adverse Reactions).