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Non-Hodgkin's Lymphoma: 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.
Severe cytokine release syndrome is characterized by severe dyspnea, often accompanied by bronchospasm and hypoxia, In addition to fever, chills, rigors, urticaria, and angioedema. Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately (see Dosage and 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 including cytokine release syndrome accompanied by hypotension and bronchospasm have been observed in 10% of patients treated with Rituximab. These symptoms are usually reversible with interruption of Rituximab infusion and administration of an antipyretic, an antihistaminic, and, occasionally, oxygen, IV saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome previously for severe reactions.
Infusion-related reactions for Rituximab: 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 Rituximab infusion, were characterized by pulmonary events and included, in some cases, rapid tumour lysis and features of tumor lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms. Patients with a high tumor 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 Rituximab therapy. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe IRRs.
Patients with a high number (> 25x109/L) of circulating malignant cells or high tumor 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 >25x109/L.
Hypersensitivity reactions/anaphylaxis: Anaphylactic and other hypersensitivity reactions have been reported following the IV administration of proteins to patients. Epinephrine, antihistamines and glucocorticoids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.
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 rtsk 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 frequently manifests itself within one or two hours of initiating the first infusion. Patients who experience severe pulmonary events should have their Rituximab administration interrupted immediately (see Dosage and 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., hyperuricaemia, hyperkalemia, hypocalcaemia, hyperphosphaetemia, 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 tumor lysis (e.g., patients with a high tumor burden or with a high number [> 25x109/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 tumor 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.
Cardiovascular: Since hypotension may occur during Rituximab administration consideration should be given to with holding antihypertensive medications 12 hours prior to and throughout Rituximab IV/SC administration. Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure or myocardial infarction have occurred in patients treated with Rituximab IV/SC. Therefore patients with a history of cardiac disease 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 < 1.5x109 /L and/or platelet counts < 75x109/L, as clinical experience with such patients is limited. Rituximab IV has been used in patients who underwent autologous bone marrow transplantation and 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 Rituximab. When Rituximab is given in combination with CHOP or CVP chemotherapy, regular full blood counts should be performed according to usual medical practice.
Infections: Rituximab 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 Rituxirnab 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.
Patients with a history of hepatitis B infection should be carefully monitored for signs of active hepatitis B infection when Rituximab is used in association with cytotoxic chemotherapy.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Rituximab. At minimum this should indude 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 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 (PML): Cases of progressive multifocal leukoencephalopathy (PML) have been reported during use of Rituximab IV in NHL and CLL. The majority of patients had received Rituximab 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. In case of such an event with a suspected relationship to Rituximab, treatment should be discontinued. Re-administration must be carefully assessed based on the individual patient's benefit-risk profile.
Immunization: The safety of immunization with live viral vaccines following Rituximab IV/SC therapy has not been studied and vaccination with live virus vaccines is not recommended. The ability to generate a primary or anamnestic humoral response to any vaccine has also not been studied.
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 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) neo-antigen (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 Rituximab IV.
